{"gene":"PANX1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2013,"finding":"Cortical spreading depression (CSD) causes neuronal PANX1 megachannel opening and subsequent caspase-1 activation, followed by HMGB1 release from neurons and NF-κB activation in astrocytes; pharmacological suppression of this cascade abolished CSD-induced trigeminovascular activation, dural mast cell degranulation, and headache.","method":"In vivo pharmacological blockade and genetic suppression in mouse model of cortical spreading depression; measurement of trigeminovascular activation, HMGB1 release, caspase-1 activity","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (pharmacological blockade, HMGB1 release assays, caspase-1 activation, trigeminovascular readouts), widely replicated in subsequent papers","pmids":["23449592"],"is_preprint":false},{"year":2017,"finding":"PANX1 forms a pore complex with P2X7 receptor; genetic loss of P2X7 or pharmacological inhibition of the P2X7-PANX1 pore complex suppresses spreading depolarization, reduces frequency and amplitude of depolarization events, and suppresses downstream neuroinflammatory gene expression (IL-1β, iNOS, COX-2) and trigeminovascular activation markers.","method":"Genetic knockout of P2x7, pharmacological pore complex inhibitors in wild-type mice and familial hemiplegic migraine mutant mice; electrophysiological thresholds, immunohistochemistry for inflammatory markers, CGRP/c-Fos expression","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological convergence across multiple readouts, replicated in multiple mouse models","pmids":["28430869"],"is_preprint":false},{"year":2010,"finding":"Intracellular cysteine 346 of PANX1 is a critical regulatory residue; C346S mutation causes constitutively active (leaky) hemichannel activity and subsequent cell death, as demonstrated by increased dye uptake and electrophysiological profiling; mutations at other intracellular cysteines did not substantially alter channel properties.","method":"Site-directed mutagenesis of PANX1 cysteine residues; dye uptake assays and electrophysiology in Xenopus oocytes and N2A cells","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with two orthogonal functional assays (dye uptake + electrophysiology), single lab","pmids":["20829356"],"is_preprint":false},{"year":2013,"finding":"The food dye FD&C Blue No. 1 (BB FCF) is a selective inhibitor of PANX1 channels with an IC50 of 0.27 µM, with no significant effect on P2X7R at concentrations up to 100 µM; the related dye FD&C Green No. 3 similarly selectively inhibited PANX1; oxidized ATP (a P2X7R antagonist) did not significantly inhibit PANX1 channels.","method":"Electrophysiological recordings and dye uptake assays in cells expressing PANX1 or P2X7R; dose-response pharmacology","journal":"Journal of General Physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology and dye uptake with dose-response, selective pharmacological characterization, single lab with multiple orthogonal methods","pmids":["23589583"],"is_preprint":false},{"year":2016,"finding":"A homozygous PANX1 missense variant p.Arg217His results in loss-of-function of the channel (assessed by dye uptake, ATP release, and electrophysiology) without affecting glycosylation or cell surface trafficking; the variant is not dominant-negative when co-expressed with wild-type PANX1; homozygosity causes multisystem dysfunction including intellectual disability, sensorineural hearing loss, skeletal defects, and primary ovarian failure.","method":"Whole exome sequencing; expression in HeLa, N2A, HEK293T, Ad293 cells; dye uptake, ATP release assays, electrophysiology; co-expression with wild-type PANX1","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — three orthogonal functional assays (dye uptake, ATP release, electrophysiology) with trafficking controls, single lab","pmids":["27129271"],"is_preprint":false},{"year":2008,"finding":"PANX1 channels make no detectable contribution to the P2X2 receptor I2 (dilated permeability) state; the I2 state is an intrinsic P2X2 property correlated with conformational changes in the cytosolic domain rather than Panx1 opening.","method":"Patch-clamp coordinated spectroscopy; tetracysteine tag/biarsenical fluorophore conformational assay; dye permeability measurements; Panx1 knockdown/inhibition","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — negative finding established by multiple orthogonal methods including novel conformational spectroscopy; mechanistically informative negative result","pmids":["18689682"],"is_preprint":false},{"year":2013,"finding":"Endogenous PANX1 interacts with actin in neural stem/progenitor cells (NSC/NPCs) and also with actin-related protein 3 (Arp3); PANX1 plays roles in NSC/NPC migration and neurite extension associated with cytoskeletal dynamics.","method":"Co-immunoprecipitation of endogenous proteins; scratch wound and neurite extension assays; Panx1 knockdown in VZ NSC/NPCs","journal":"Cell Communication and Signaling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — endogenous Co-IP identifying two binding partners (actin and Arp3), functional assays with knockdown, single lab","pmids":["23964896"],"is_preprint":false},{"year":2014,"finding":"PANX1 controls cellular properties of keratinocytes and dermal fibroblasts; Panx1 KO fibroblasts show increased proliferation, reduced collagen gel contraction comparable to probenecid-treated WT fibroblasts, and fail to upregulate α-smooth muscle actin in response to TGF-β (a marker of myofibroblast differentiation); Panx1 KO keratinocytes are more migratory; Panx1 KO mice show delayed wound healing and altered skin thickness.","method":"Panx1 KO mouse model; histology; scratch wound assays; proliferation assays; collagen gel contraction; TGF-β stimulation; pharmacological blockade with probenecid","journal":"Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO combined with pharmacological validation (probenecid), multiple cell-type specific phenotypic readouts, single lab","pmids":["24522432"],"is_preprint":false},{"year":2016,"finding":"P2X7R and PANX1 are co-expressed in osteocytes and together form a major pathway for flow-induced ATP release in bone mechanosignaling; high glucose conditions (simulating type 1 diabetes) blunt P2X7R- and flow-induced Ca2+ signaling and ATP release from osteocytes, associated with altered P2X7R and PANX1 expression.","method":"Western blot for co-expression; oscillatory fluid shear stress assays; Ca2+ response measurements; ATP release measurements; diabetic mouse model (Akita); high glucose cell culture","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-expression established, functional ATP release and Ca2+ signaling assays, both in vitro and in vivo, single lab","pmids":["27159053"],"is_preprint":false},{"year":2021,"finding":"PANX1 channels in microglia release purines that activate microglial P2RY12 receptors; P2RY12 signaling regulates capillary-associated microglia (CAM) interactions with brain capillaries; PANX1-/- and P2RY12-/- mice show capillary dilation, increased blood flow, and impaired vasodilation, phenocopying microglial depletion.","method":"PANX1-/- and P2RY12-/- mouse models; microglial depletion; morphological/ultrastructural analysis; blood flow measurements; pharmacological assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — convergent genetic evidence from two KO lines plus microglial depletion, multiple vascular readouts, establishes PANX1-P2RY12 coupling mechanism","pmids":["34489419"],"is_preprint":false},{"year":2022,"finding":"TLR2 activation in macrophages by danger signals from necrotic tubular epithelial cells activates PANX1 channels via caspase-5, leading to ATP secretion through PANX1 and subsequent NLRP3 inflammasome activation; this TLR2/caspase-5/Panx1 axis drives necroinflammation in acute kidney injury.","method":"Conditioned medium from necrotic TECs applied to macrophages; siRNA knockdown of Panx1, TLR2, caspase-5; NLRP3 inflammasome activation assays; ATP measurement","journal":"Cell Death Discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown of three pathway components with defined phenotypic readout, single lab","pmids":["35473933"],"is_preprint":false},{"year":2024,"finding":"TNFα promotes PANX1 cleavage via a caspase 8/3-dependent pathway in colorectal cancer cells, enhancing ATP release; this ATP release through PANX1 activates P2RX7 receptor-mediated antitumor immunity, including dendritic cell maturation and T-cell activation during chemotherapy-induced immunogenic cell death.","method":"PANX1 cleavage assay; caspase inhibitor experiments; ATP release measurements; immune cell activation assays in vitro and in vivo; P2RX7 blockade","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (caspase pathway, ATP release, immune activation) with pharmacological blockade, single lab","pmids":["38195677"],"is_preprint":false},{"year":2019,"finding":"PANX1 in polarized MDCK cells is preferentially delivered to the apical membrane domain; the cell-surface targeting domain maps to residues 307–379; a Y308F mutation (disrupting a putative YxxΦ basolateral sorting motif) or a Δ379 truncation causes MDCK cells to lose cell-cell contacts and polarization capacity, switching to a fibroblast-like phenotype.","method":"GFP-tagged Panx1 in polarized MDCK cells and BICR-M1Rk cells; domain deletion and point mutagenesis; live-cell imaging; immunofluorescence; spheroid culture","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with localization and phenotypic readouts, single lab, multiple constructs tested","pmids":["31102595"],"is_preprint":false},{"year":2024,"finding":"PANX1-mediated ATP release is required for FAM3A's suppression of hepatic gluconeogenesis and lipogenesis; mechanistically, PANX1-released ATP activates P2Y receptors to inhibit gluconeogenesis via the Akt-FOXO1 pathway; PANX1-released ATP also activates calmodulin (CaM), which interacts with JNK to inhibit AP1 transcription factor and repress FAS expression and lipogenesis; FAM3A stimulates PANX1 expression via HSF1; FAM3A overexpression fails to suppress gluconeogenesis/lipogenesis in PANX1-deficient hepatocytes.","method":"Co-immunoprecipitation with MS; PANX1 global KO mice; adenovirus/AAV gene overexpression/knockdown in vivo; OGTT, PTT, ITT metabolic tests; ATP release measurements; Western blot","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS to identify interactions, genetic KO rescue experiments, multiple metabolic phenotype readouts, single lab","pmids":["38937853"],"is_preprint":false},{"year":2024,"finding":"Non-ionotropic NMDA receptor (niNMDAR) signaling activates PANX1 via Src kinase; PANX1 releases ATP (but is not permeable to Ca2+) to activate P2X4 purinergic receptors, producing long-term depression (LTD) at CA3-CA1 hippocampal synapses following low-frequency stimulation.","method":"Whole-cell patch-clamp electrophysiology in rat hippocampal slices; competitive NMDAR antagonist (MK-801) applied transiently vs continuously; pharmacological blockade of Panx1 (with rescue by exogenous ATP); P2X4 antagonist (5-BDBD); Src kinase inhibitors","journal":"Journal of Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with multiple pharmacological dissection, ATP rescue experiment, single lab","pmids":["39709529"],"is_preprint":false},{"year":2023,"finding":"Both astrocyte and neuronal PANX1 are required for long-term spatial reference memory but not spatial working memory in mice; global Panx1 deletion attenuates LTP and LTD at Schaffer collateral-CA1 synapses without altering basal synaptic transmission or paired-pulse facilitation.","method":"Global and cell-type specific Panx1 transgenic KO mice; 8-arm radial maze; hippocampal slice field potential recordings; LTP and LTD induction protocols","journal":"ASN Neuro","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic dissection using cell-type specific KO combined with behavioral and electrophysiological readouts, single lab with multiple orthogonal approaches","pmids":["37365910"],"is_preprint":false},{"year":2021,"finding":"Homozygous PANX1 missense variants (p.Ser238Pro and p.Arg300Gln) alter PANX1 glycosylation pattern in cultured cells, cause aberrant PANX1 channel activation, and result in mouse oocyte death after in vitro fertilization; these variants follow autosomal recessive inheritance and cause female infertility.","method":"Whole exome sequencing; Western blot for glycosylation; electrophysiology and dye uptake for channel function; in vitro fertilization mouse oocyte assay","journal":"European Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — variant characterization using glycosylation, electrophysiology, and in vivo oocyte model, single lab","pmids":["33495594"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structural analysis reveals that PANX1 channel permeation selectivity is controlled by structural plasticity at the extracellular entrance formed by seven W74 residues; W74 side chains sample conformations from a constricted state permissive to chloride only, to a dilated state compatible with ATP; these states are coupled to variable cation-π interactions between W74 and R75; mefloquine acts as a positive modulator binding near the side tunnel to enhance ion flow.","method":"Cryo-EM structure determination; molecular dynamics/conformational analysis; mutagenesis (W74, R75); electrophysiology with mefloquine","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with mutagenesis and electrophysiological validation, defining structural basis of permeation and modulation, single lab","pmids":["41381453"],"is_preprint":false},{"year":2025,"finding":"A metastasis-associated N-terminal truncation mutant Panx1(1-89) forms a constitutively active membrane channel capable of releasing ATP independently of full-length PANX1; basic structure-function features of the channel pore are conserved; elevated extracellular K+ enhances Panx1(1-89)-mediated conductance; the truncated channel retains sensitivity to most full-length PANX1 inhibitors.","method":"Electrophysiology; ATP release assays; pharmacological inhibitor profiling; extracellular K+ stimulation experiments in cells expressing Panx1(1-89)","journal":"FEBS Journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — electrophysiology and ATP release with multiple inhibitor tests, single lab","pmids":["40087867"],"is_preprint":false},{"year":2025,"finding":"ATP stimulates macropinocytosis in Neuro2a neuroblastoma cells, driving cell size increase and PANX1 internalization to macropinosomes; mutation of extracellular tryptophan W74 in PANX1 abolishes ATP-evoked cell area enlargement; ARF6(Q67L) expression phenocopies ATP-induced PANX1 internalization; PI3K inhibition, actin disruption, and GTPase inhibition abolish ATP-induced PANX1 internalization.","method":"Cell area measurement; fluorescent PANX1 constructs; W74 mutagenesis; ARF6 Q67L expression; pharmacological inhibitors of PI3K, actin polymerization; co-localization with macropinosomal cargo","journal":"Biology Open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with multiple inhibitor approaches and compartment co-localization, single lab","pmids":["41250870"],"is_preprint":false},{"year":2024,"finding":"Raptinal simultaneously induces apoptosis and inhibits caspase-activated PANX1 via a mechanism distinct from carbenoxolone and trovafloxacin; PANX1 inhibition by raptinal suppresses ATP 'find-me' signal release, formation of apoptotic cell-derived extracellular vesicles, and NLRP3 inflammasome activation.","method":"Biochemical, cell biological, and electrophysiological approaches; caspase activation assays; PANX1 cleavage assays; ATP release; extracellular vesicle quantification; NLRP3 inflammasome assay; comparison with known inhibitors","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, biochemistry, functional assays), single lab","pmids":["38336804"],"is_preprint":false},{"year":2024,"finding":"PANX1 deletion in cardiomyocytes increases glycolytic metabolism and glycolytic ATP production with concurrent decrease in oxidative phosphorylation; isoproterenol treatment of cardiomyocytes induces PANX1-dependent ATP release and Yo-Pro-1 uptake; cardiomyocyte-specific Panx1 KO mice are protected from isoproterenol-induced cardiac hypertrophy and show decreased immune cell (particularly neutrophil) recruitment to myocardium.","method":"Cardiomyocyte-specific Panx1 KO mouse (Panx1MyHC6); metabolic flux analysis in vivo and in vitro; isoproterenol treatment; spironolactone and siRNA-mediated PANX1 blockade; Yo-Pro-1 uptake; flow cytometry for immune cells","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type specific genetic KO with pharmacological and siRNA validation, multiple orthogonal metabolic and immune readouts, single lab","pmids":["38957990"],"is_preprint":false},{"year":2022,"finding":"Human and mouse PANX1 orthologs differ in activation mechanisms: human PANX1 is insensitive to stimulation with high extracellular [K+] but responds to P2X7 receptor activation, while mouse PANX1 responds to both stimuli; human PANX1 polymorphism Q5H (rs1138800) is a gain-of-function and E390D (rs74549886) is a loss-of-function variant for P2X7-mediated channel activation.","method":"Dye uptake and electrophysiology in N2a neuroblastoma cells expressing endogenous mPanx1 or exogenous hPanx1; human PANX1 polymorphic variants expressed in Panx1-null cells; high K+ stimulation; P2X7 receptor activation","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — electrophysiology and dye uptake with multiple variants and stimuli, single lab","pmids":["38100403"],"is_preprint":false},{"year":2022,"finding":"Cholesterol depletion (by methyl-β-cyclodextrin) and inhibition of cholesterol synthesis (lovastatin) decrease lateral diffusion of PANX1 in the plasma membrane (assessed by FRAP) while enhancing PANX1 channel activity (dye uptake, ATP release, ionic current) in cholesterol-depleted astrocytes and PANX1-transfected cells.","method":"FRAP for membrane mobility; electrophysiology; dye uptake; ATP release assays; pharmacological cholesterol manipulation in astrocytes and transfected cells","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP localization linked to function via multiple activity assays, single lab","pmids":["36291086"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, Panx1a and Panx1b (both homologous to human PANX1) exert dual pro- and anti-seizure activities via ATP release and P2rx7 receptor signaling; loss of Panx1a function reduces ictal-like events and seizure-like locomotion induced by pentylenetetrazol; transcriptome profiling reveals distinct metabolic and cell-signaling states associated with loss of Panx1a.","method":"Genetic KO (panx1a-/-) and pharmacological blockade of Panx1a/Panx1b in zebrafish larvae; electrophysiology; behavioral analysis; RNA-seq; ATP release measurements","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent genetic and pharmacological evidence in zebrafish with electrophysiological and transcriptomic readouts, single lab","pmids":["35585187"],"is_preprint":false},{"year":2017,"finding":"cAMP-mediated pathway does NOT drive ATP release from red blood cells (RBCs) through PANX1; Panx1-/- mice show no decrease in exercise performance; treatment with stable cAMP analog does not induce ATP release from WT or Panx1-/- RBCs; multiple pharmacological AC activators increase intracellular cAMP but do not induce ATP release.","method":"Panx1-/- mouse model; exercise performance testing; RBC ex vivo ATP release assays; cAMP measurement by mass spectrometry; pharmacological adenylate cyclase activation","journal":"American Journal of Physiology - Cell Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistically informative negative finding using genetic KO plus multiple pharmacological tools with quantitative cAMP measurement, single lab","pmids":["28855161"],"is_preprint":false},{"year":2024,"finding":"Neuronal PANX1 drives peripheral sensitization in inflammatory pain through cell-autonomous effects on neuronal excitability; neuron-specific Panx1 KO reduces pain sensitivity after CFA-induced inflammation; neuronal Panx1 enhances DRG neuron response to ATP; Panx1 supports Wnt/β-catenin-dependent DRG neurogenesis; ATP release from Panx1 channels increases Ca2+ responses in DRGNs and satellite glial cells.","method":"Global and neuron-specific Panx1 KO mice; von Frey test after CFA injection; confocal microscopy; Sholl analysis; electrophysiology in Neuro2a and DRG neurons; ethidium bromide dye uptake; calcium imaging; β-galactosidase staining in transgenic mice","journal":"Military Medical Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type specific genetic KO with multiple orthogonal mechanistic assays (electrophysiology, Ca2+ imaging, dye uptake, neurogenesis markers), single lab","pmids":["38685116"],"is_preprint":false},{"year":2024,"finding":"PANX1 variants (p.Ser137Leu and p.Asn326del) alter PANX1 glycosylation, cause aberrant channel activation, affect ATP release and membrane electrophysiological properties, and result in human and mouse oocyte death in vitro; both variants follow autosomal dominant inheritance.","method":"Whole exome sequencing; Western blot for glycosylation; ATP release measurement; electrophysiology; in vitro mouse and human oocyte fertilization assay","journal":"Journal of Ovarian Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (glycosylation, electrophysiology, ATP release) validated with human oocyte data, single lab","pmids":["39232764"],"is_preprint":false},{"year":2025,"finding":"TGM2 interacts with PANX1 (co-immunoprecipitation); TGM2-PANX1 interaction promotes lipid deposition; knockdown or pharmacological inhibition of PANX1 decreases levels of PPARα and PANK1 induced by adriamycin, suggesting PANX1 operates downstream of TGM2 in a pathway regulating lipid metabolism.","method":"Co-immunoprecipitation; siRNA knockdown of PANX1; Western blot for PPARα and PANK1; adriamycin nephropathy cell and mouse model; YR-7 peptide treatment","journal":"Translational Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying TGM2-PANX1 interaction, downstream pathway placement based on knockdown with one cell model, single lab","pmids":["38734063"],"is_preprint":false},{"year":2024,"finding":"PANX1 channel activity is required for endometrial decidualization: PANX1 overexpression in human endometrial stromal cells (HESCs) increases extracellular ATP and impairs decidualization markers (PRL, IGFBP-1) and cytoskeletal morphology; PANX1 knockdown also impairs decidualization, indicating that normal PANX1 expression level is required; this mechanism is associated with recurrent implantation failure.","method":"PANX1 plasmid overexpression and siRNA knockdown in HESCs; extracellular ATP detection; Western blot for PRL and IGFBP-1; immunofluorescence for cytoskeleton; animal model validation","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with functional decidualization readouts and in vivo validation, single lab","pmids":["41775813"],"is_preprint":false}],"current_model":"PANX1 is a large-pore ATP release channel whose gating is structurally controlled by conformational flexibility at extracellular W74 residues (cryo-EM), regulated by intracellular C346, and activated downstream of P2X7 receptor, Src kinase, caspase cleavage, and mechanical stimuli; it forms functional complexes with P2X7R and signals through released ATP to P2RY12 and P2X4 receptors, driving diverse processes including neuroinflammation (via caspase-1/HMGB1 in cortical spreading depression), synaptic plasticity (LTP/LTD), pain sensitization, oocyte development, cardiac metabolism and hypertrophy, immune cell recruitment, and skin/mammary tissue homeostasis, while pathogenic gain- or loss-of-function PANX1 variants disrupt glycosylation and channel activity to cause human disease including female infertility and multisystem disorders."},"narrative":{"mechanistic_narrative":"PANX1 is a large-pore plasma membrane channel that mediates regulated release of ATP, coupling diverse cellular stimuli to purinergic signaling across the nervous, immune, metabolic, and reproductive systems [PMID:23449592, PMID:39709529, PMID:38957990]. Cryo-EM defines the structural basis of its permeation: an extracellular constriction formed by seven W74 residues samples conformations ranging from a chloride-only state to a dilated, ATP-permeant state, with cation-π interactions between W74 and R75 controlling selectivity and the antimalarial mefloquine acting as a positive modulator [PMID:41381453]. Channel gating is further controlled by an intracellular regulatory cysteine (C346), whose mutation produces a constitutively leaky, cytotoxic channel [PMID:20829356]. PANX1 is activated through multiple convergent routes—physical and functional coupling to the P2X7 receptor [PMID:28430869, PMID:38100403], Src kinase downstream of non-ionotropic NMDA receptors [PMID:39709529], and caspase-dependent cleavage (caspase-1, caspase-5, caspase-8/3, and an N-terminal truncation that yields a constitutively active fragment) [PMID:35473933, PMID:38195677, PMID:40087867]—and the released ATP signals onward to purinergic receptors including P2RY12, P2X4, and P2X7 [PMID:34489419, PMID:39709529, PMID:38195677]. Through this ATP-release function PANX1 drives neuroinflammation in cortical spreading depression via a caspase-1/HMGB1 cascade [PMID:23449592], hippocampal LTP and LTD underlying spatial memory [PMID:39709529, PMID:37365910], peripheral pain sensitization [PMID:38685116], cardiomyocyte metabolism and isoproterenol-induced hypertrophy [PMID:38957990], inflammasome-dependent injury responses [PMID:35473933, PMID:38336804], and tissue homeostasis in skin, bone, and the endometrium [PMID:24522432, PMID:27159053, PMID:41775813]. Homozygous and dominant PANX1 variants that disrupt glycosylation and cause aberrant channel activation produce female infertility through oocyte death, and a loss-of-function variant causes a multisystem disorder with intellectual disability, sensorineural hearing loss, skeletal defects, and primary ovarian failure [PMID:27129271, PMID:33495594, PMID:39232764].","teleology":[{"year":2008,"claim":"Established that PANX1 is not responsible for the P2X2 receptor dilated-permeability (I2) state, distinguishing intrinsic receptor conformational change from pannexin channel opening and constraining how PANX1 is invoked in purinergic permeability.","evidence":"Patch-clamp coordinated spectroscopy and conformational fluorophore assays with Panx1 knockdown","pmids":["18689682"],"confidence":"High","gaps":["Does not address PANX1 coupling to other P2X subtypes","Negative result for one receptor only"]},{"year":2010,"claim":"Identified intracellular cysteine 346 as a critical gating residue, showing PANX1 channel opening is tightly regulated and that loss of this control produces a leaky, lethal channel.","evidence":"Site-directed mutagenesis with dye uptake and electrophysiology in Xenopus oocytes and N2A cells","pmids":["20829356"],"confidence":"High","gaps":["Physiological modification controlling C346 not defined","No structural model of the closed state"]},{"year":2013,"claim":"Linked neuronal PANX1 megachannel opening to a defined neuroinflammatory cascade (caspase-1/HMGB1/NF-κB) driving headache, establishing PANX1 as an upstream trigger of trigeminovascular activation.","evidence":"In vivo pharmacological blockade and genetic suppression in a mouse cortical spreading depression model","pmids":["23449592"],"confidence":"High","gaps":["Stimulus coupling PANX1 to caspase-1 not resolved at molecular level"]},{"year":2013,"claim":"Provided a selective small-molecule tool (BB FCF) distinguishing PANX1 from P2X7R pharmacologically, enabling clean dissection of PANX1-specific contributions.","evidence":"Dose-response electrophysiology and dye uptake in PANX1- vs P2X7R-expressing cells","pmids":["23589583"],"confidence":"High","gaps":["In vivo selectivity and potency not established"]},{"year":2013,"claim":"Connected PANX1 to cytoskeletal machinery by demonstrating endogenous interaction with actin and Arp3 and roles in neural progenitor migration, hinting at channel-independent or cytoskeleton-coupled functions.","evidence":"Endogenous co-immunoprecipitation with scratch-wound and neurite assays under Panx1 knockdown","pmids":["23964896"],"confidence":"Medium","gaps":["Direct vs indirect actin/Arp3 binding not resolved","Whether migration phenotype depends on channel activity unknown"]},{"year":2014,"claim":"Defined a homeostatic role for PANX1 in skin, regulating fibroblast contraction, myofibroblast differentiation, keratinocyte migration, and wound healing.","evidence":"Panx1 KO mice and probenecid blockade with proliferation, collagen contraction, and TGF-β assays","pmids":["24522432"],"confidence":"High","gaps":["Downstream purinergic receptor in skin not identified"]},{"year":2016,"claim":"Identified a human loss-of-function PANX1 variant (R217H) causing a multisystem disorder, providing the first direct gene-disease link and showing the channel defect is recessive and trafficking-independent.","evidence":"Whole exome sequencing with dye uptake, ATP release, electrophysiology, and trafficking controls","pmids":["27129271"],"confidence":"High","gaps":["Tissue-specific basis of each multisystem phenotype not dissected"]},{"year":2016,"claim":"Showed P2X7R-PANX1 co-expression mediates flow-induced ATP release in osteocyte mechanosignaling, extending PANX1 to bone and showing hyperglycemia blunts this pathway.","evidence":"Western blot co-expression, fluid shear stress, Ca2+ and ATP assays in a diabetic mouse model","pmids":["27159053"],"confidence":"Medium","gaps":["Direct physical PANX1-P2X7 complex in osteocytes not shown","Single lab"]},{"year":2017,"claim":"Demonstrated PANX1 forms a functional pore complex with P2X7R that drives spreading depolarization and neuroinflammation, mechanistically linking the two channels.","evidence":"P2x7 knockout and pore-complex inhibitors in wild-type and familial hemiplegic migraine mutant mice","pmids":["28430869"],"confidence":"High","gaps":["Stoichiometry and structural interface of the complex not defined"]},{"year":2017,"claim":"Excluded a cAMP-PANX1 pathway for ATP release from red blood cells, refining the contexts in which PANX1 mediates ATP efflux.","evidence":"Panx1-/- mice, exercise testing, RBC ATP release, and cAMP mass spectrometry with AC activators","pmids":["28855161"],"confidence":"Medium","gaps":["Does not rule out PANX1 ATP release via other RBC stimuli"]},{"year":2019,"claim":"Mapped a C-terminal surface-targeting domain (307–379) and a YxxΦ sorting motif controlling apical PANX1 delivery and epithelial polarity, linking PANX1 trafficking to cell-cell contact maintenance.","evidence":"GFP-PANX1 domain deletion and Y308F mutagenesis in polarized MDCK cells with imaging","pmids":["31102595"],"confidence":"Medium","gaps":["Whether polarity phenotype requires channel activity unknown","Single lab"]},{"year":2021,"claim":"Established PANX1-P2RY12 coupling in microglia controlling capillary interactions and cerebral blood flow, defining a discrete neurovascular signaling axis.","evidence":"PANX1-/- and P2RY12-/- mice, microglial depletion, and blood flow measurements","pmids":["34489419"],"confidence":"High","gaps":["Specific purine released and its receptor binding kinetics not defined"]},{"year":2021,"claim":"Identified recessive PANX1 variants (S238P, R300Q) that alter glycosylation and cause aberrant activation leading to oocyte death and female infertility, establishing PANX1 in reproduction.","evidence":"Whole exome sequencing, glycosylation Western blot, electrophysiology, and IVF oocyte assays","pmids":["33495594"],"confidence":"Medium","gaps":["Mechanistic link between altered glycosylation and oocyte death not resolved"]},{"year":2022,"claim":"Revealed species-specific PANX1 activation—human PANX1 responds to P2X7 but not high K+—and human polymorphisms (Q5H gain-, E390D loss-of-function), clarifying translational caveats and natural functional variation.","evidence":"Dye uptake and electrophysiology comparing mouse and human PANX1 and polymorphic variants in Panx1-null cells","pmids":["38100403"],"confidence":"Medium","gaps":["Structural basis of species difference in K+ sensitivity not defined"]},{"year":2022,"claim":"Linked plasma membrane cholesterol to PANX1 lateral mobility and activity, showing cholesterol depletion enhances channel function while reducing diffusion.","evidence":"FRAP, electrophysiology, dye uptake, and ATP release with cholesterol manipulation in astrocytes","pmids":["36291086"],"confidence":"Medium","gaps":["Whether cholesterol binds PANX1 directly unknown"]},{"year":2022,"claim":"Showed PANX1 orthologs exert dual pro- and anti-seizure roles via ATP/P2rx7 signaling in zebrafish, broadening understanding of PANX1 in excitability.","evidence":"panx1a-/- and pharmacological blockade in zebrafish larvae with electrophysiology, behavior, and RNA-seq","pmids":["35585187"],"confidence":"Medium","gaps":["Mechanism reconciling opposing pro/anti-seizure effects not resolved"]},{"year":2022,"claim":"Defined a TLR2/caspase-5/PANX1 axis in macrophages connecting necrotic cell danger signals to ATP secretion and NLRP3 inflammasome activation in kidney injury.","evidence":"Conditioned medium from necrotic tubular cells with siRNA knockdown of Panx1, TLR2, caspase-5","pmids":["35473933"],"confidence":"Medium","gaps":["Direct caspase-5 cleavage site on PANX1 not mapped"]},{"year":2023,"claim":"Demonstrated both neuronal and astrocytic PANX1 are required for hippocampal LTP/LTD and long-term spatial memory, establishing a cognitive role for the channel.","evidence":"Global and cell-type specific Panx1 KO mice with radial maze and field potential recordings","pmids":["37365910"],"confidence":"High","gaps":["Molecular link between PANX1 ATP release and plasticity machinery not fully resolved"]},{"year":2024,"claim":"Resolved a niNMDAR→Src→PANX1→ATP→P2X4 pathway producing hippocampal LTD, defining a precise signaling chain for PANX1 in synaptic depression.","evidence":"Patch-clamp in hippocampal slices with NMDAR, Src, PANX1, and P2X4 pharmacology plus ATP rescue","pmids":["39709529"],"confidence":"Medium","gaps":["How Src activation gates PANX1 structurally not shown"]},{"year":2024,"claim":"Showed neuronal PANX1 drives inflammatory pain cell-autonomously by enhancing DRG excitability and supporting Wnt/β-catenin neurogenesis, placing PANX1 in peripheral sensitization.","evidence":"Global and neuron-specific Panx1 KO mice with von Frey, electrophysiology, Ca2+ imaging, and neurogenesis markers","pmids":["38685116"],"confidence":"High","gaps":["Relative contributions of channel ATP release vs neurogenesis to pain not separated"]},{"year":2024,"claim":"Defined a cardiomyocyte metabolic and immune role for PANX1, with deletion shifting metabolism toward glycolysis and protecting against isoproterenol-induced hypertrophy and neutrophil recruitment.","evidence":"Cardiomyocyte-specific Panx1 KO mice with metabolic flux, Yo-Pro-1 uptake, and flow cytometry","pmids":["38957990"],"confidence":"High","gaps":["Mechanism linking PANX1 ATP release to metabolic substrate switching not resolved"]},{"year":2024,"claim":"Identified a TNFα→caspase-8/3→PANX1 cleavage pathway enhancing ATP release that activates P2RX7-mediated antitumor immunity during immunogenic cell death.","evidence":"PANX1 cleavage and ATP release assays with caspase inhibitors and immune activation readouts in colorectal cancer models","pmids":["38195677"],"confidence":"Medium","gaps":["In vivo contribution to clinical immunotherapy response not established"]},{"year":2024,"claim":"Placed PANX1 ATP release downstream of FAM3A to suppress hepatic gluconeogenesis (P2Y/Akt-FOXO1) and lipogenesis (CaM/JNK/AP1), defining a hepatic metabolic signaling node.","evidence":"Co-IP/MS, global Panx1 KO and rescue, and in vivo metabolic testing","pmids":["38937853"],"confidence":"Medium","gaps":["Direct vs autocrine purinergic step in hepatocytes not isolated"]},{"year":2024,"claim":"Demonstrated a narrow expression window for PANX1 in endometrial decidualization, with both overexpression and knockdown impairing decidualization markers, linking PANX1 to implantation failure.","evidence":"Bidirectional PANX1 manipulation in human endometrial stromal cells with decidualization markers and ATP measurement","pmids":["41775813"],"confidence":"Medium","gaps":["Downstream purinergic receptor in endometrium not identified"]},{"year":2024,"claim":"Identified raptinal as an inhibitor of caspase-activated PANX1 acting by a distinct mechanism, suppressing apoptotic 'find-me' ATP signals, extracellular vesicle formation, and NLRP3 activation.","evidence":"Electrophysiology, biochemistry, ATP release, EV quantification, and NLRP3 assays versus known inhibitors","pmids":["38336804"],"confidence":"Medium","gaps":["Binding site of raptinal on PANX1 not mapped"]},{"year":2024,"claim":"Identified dominant PANX1 variants (S137L, N326del) altering glycosylation and channel activation that cause oocyte death and infertility, expanding the inheritance modes of PANX1 reproductive disease.","evidence":"Whole exome sequencing with glycosylation, electrophysiology, ATP release, and human/mouse oocyte IVF assays","pmids":["39232764"],"confidence":"Medium","gaps":["Dominant mechanism (gain-of-function vs dominant-negative) not formally resolved"]},{"year":2024,"claim":"Proposed PANX1 acts downstream of TGM2 to promote lipid deposition in nephropathy, placing PANX1 in a renal lipid metabolism pathway.","evidence":"Co-immunoprecipitation, siRNA knockdown, and PPARα/PANK1 Western blot in adriamycin nephropathy models","pmids":["38734063"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","Pathway placement from one cell model only"]},{"year":2025,"claim":"Defined the structural basis of PANX1 permeation selectivity at near-atomic resolution, showing W74 conformational plasticity and W74-R75 cation-π interactions gate the channel between chloride-only and ATP-permeant states, with mefloquine as a positive modulator.","evidence":"Cryo-EM structure determination with conformational analysis, W74/R75 mutagenesis, and mefloquine electrophysiology","pmids":["41381453"],"confidence":"High","gaps":["How upstream activators (P2X7, Src, caspase) drive W74 conformational change not shown"]},{"year":2025,"claim":"Showed an N-terminal truncation mutant Panx1(1-89) forms a constitutively active, K+-enhanced ATP-releasing channel that retains inhibitor sensitivity, linking PANX1 fragments to metastasis.","evidence":"Electrophysiology, ATP release, inhibitor profiling, and high-K+ stimulation of Panx1(1-89)-expressing cells","pmids":["40087867"],"confidence":"Medium","gaps":["In vivo generation and metastatic mechanism of the truncation not established"]},{"year":2025,"claim":"Demonstrated ATP-driven macropinocytosis internalizes PANX1 via a W74-, ARF6-, PI3K-, and actin-dependent route, revealing feedback regulation of channel surface levels.","evidence":"Cell area measurement, W74 mutagenesis, ARF6(Q67L) expression, and PI3K/actin/GTPase inhibitors with macropinosome co-localization in Neuro2a cells","pmids":["41250870"],"confidence":"Medium","gaps":["Physiological trigger and consequence of PANX1 internalization in vivo unknown"]},{"year":null,"claim":"How the distinct upstream activators (P2X7 complex formation, Src phosphorylation, caspase cleavage, mechanical and lipid-environment cues) converge to drive the W74/R75 conformational transition that opens the ATP-permeant pore remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of an activated, P2X7-bound or Src-phosphorylated PANX1","Coupling between cleavage events and the W74 gate not mapped","How glycosylation status biochemically controls gating unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,4,17,18,22]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,12,17,23]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,14]},{"term_id":"R-HSA-168256","term_label":"Immune 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Forms anion-selective channels with relatively low conductance and an order of permeabilities: nitrate>iodide>chlroride>>aspartate=glutamate=gluconate (By similarity). Can release ATP upon activation through phosphorylation or cleavage at C-terminus (PubMed:32238926). May play a role as a Ca(2+)-leak channel to regulate ER Ca(2+) homeostasis (PubMed:16908669) During apoptosis, the C terminal tail is cleaved by caspases, which opens the main pore acting as a large-pore ATP efflux channel with a broad distribution, which allows the regulated release of molecules and ions smaller than 1 kDa, such as nucleotides ATP and UTP, and selective plasma membrane permeability to attract phagocytes that engulf the dying cells","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96RD7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PANX1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PANX1","total_profiled":1310},"omim":[{"mim_id":"618550","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 7; OZEMA7","url":"https://www.omim.org/entry/618550"},{"mim_id":"615774","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 1; OZEMA1","url":"https://www.omim.org/entry/615774"},{"mim_id":"608422","title":"PANNEXIN 3; PANX3","url":"https://www.omim.org/entry/608422"},{"mim_id":"608421","title":"PANNEXIN 2; PANX2","url":"https://www.omim.org/entry/608421"},{"mim_id":"608420","title":"PANNEXIN 1; PANX1","url":"https://www.omim.org/entry/608420"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue 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Blocks Panx1 Channels and Reduces Ischemic Brain Infarct in a Dose- and Sex-Dependent Way.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39271622","citation_count":3,"is_preprint":false},{"pmid":"374992","id":"PMC_374992","title":"Cis- and trans-activity of P22 antirepressor protein against c-repression specified by the closely related Salmonella phages L and Px1.","date":"1979","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/374992","citation_count":3,"is_preprint":false},{"pmid":"40978734","id":"PMC_40978734","title":"The impact of Panx1 on inflammation, immunity, and cancer: a comprehensive review.","date":"2025","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40978734","citation_count":2,"is_preprint":false},{"pmid":"36711845","id":"PMC_36711845","title":"Astrocyte and neuronal Panx1 support long-term reference memory in mice.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711845","citation_count":2,"is_preprint":false},{"pmid":"40087867","id":"PMC_40087867","title":"A metastasis-associated pannexin-1 mutant (Panx11-89) forms a minimalist ATP release channel.","date":"2025","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/40087867","citation_count":2,"is_preprint":false},{"pmid":"37594023","id":"PMC_37594023","title":"Panx1 knockout promotes preneoplastic aberrant crypt foci development in a chemically induced model of mouse colon carcinogenesis.","date":"2023","source":"International journal of experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37594023","citation_count":2,"is_preprint":false},{"pmid":"40783103","id":"PMC_40783103","title":"Metabolomics and mass spectrometry imaging reveal the effect of Prunella vulgaris oil on chronic pelvic inflammatory disease: Exploring the mechanism from inhibition of PANX1.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40783103","citation_count":2,"is_preprint":false},{"pmid":"39090420","id":"PMC_39090420","title":"Novel genetic variants in the NLRP3 inflammasome-related PANX1 and APP genes predict survival of patients with hepatitis B virus-related hepatocellular carcinoma.","date":"2024","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/39090420","citation_count":2,"is_preprint":false},{"pmid":"38100403","id":"PMC_38100403","title":"Differential activation of mouse and human Panx1 channel variants.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38100403","citation_count":1,"is_preprint":false},{"pmid":"41351813","id":"PMC_41351813","title":"Tanshinone IIA Inhibits Microglial Activation and Inflammation and Relieves Cerebral Ischemia‒Reperfusion Injury Through TGM2/PANX1.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41351813","citation_count":1,"is_preprint":false},{"pmid":"36131672","id":"PMC_36131672","title":"[Colonization performance and pyrene degradation characteristics of Stenotrophomonas maltophilia PX1].","date":"2022","source":"Ying yong sheng tai xue bao = The journal of applied ecology","url":"https://pubmed.ncbi.nlm.nih.gov/36131672","citation_count":1,"is_preprint":false},{"pmid":"39334824","id":"PMC_39334824","title":"Cold Exposure Rejuvenates the Metabolic Phenotype of Panx1 Mice.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39334824","citation_count":1,"is_preprint":false},{"pmid":"38860607","id":"PMC_38860607","title":"Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38860607","citation_count":1,"is_preprint":false},{"pmid":"41381453","id":"PMC_41381453","title":"Structural basis of PANX1 permeation and positive modulation by mefloquine.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41381453","citation_count":1,"is_preprint":false},{"pmid":"30698564","id":"PMC_30698564","title":"[Sleep-wake cycle and experimental models of Panx1 mutations].","date":"2018","source":"Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova","url":"https://pubmed.ncbi.nlm.nih.gov/30698564","citation_count":1,"is_preprint":false},{"pmid":"40827894","id":"PMC_40827894","title":"The Synergistic Role of P2rx7 and Panx1 in Regulating Alveolar Macrophage Pyroptosis and Exosome-Mediated Ferroptosis of Alveolar Epithelial Cells in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40827894","citation_count":0,"is_preprint":false},{"pmid":"41197910","id":"PMC_41197910","title":"Electroacupuncture ameliorates mitochondrial dysfunction and alleviates traumatic brain injury via the PANX1/ATP/Ca2+ pathway.","date":"2025","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/41197910","citation_count":0,"is_preprint":false},{"pmid":"41250870","id":"PMC_41250870","title":"ATP increases murine neuroblastoma cell size through a PANX1- and macropinocytosis-dependent mechanism.","date":"2025","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/41250870","citation_count":0,"is_preprint":false},{"pmid":"41765358","id":"PMC_41765358","title":"PANX1-mediated NLRP3 inflammasome activation promotes an adaptive doxorubicin resistance through IL-1β signaling in breast cancer.","date":"2026","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41765358","citation_count":0,"is_preprint":false},{"pmid":"38559162","id":"PMC_38559162","title":"A metastasis-associated Pannexin1 mutant (Panx1 1-89 ) forms a minimalist ATP release channel.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38559162","citation_count":0,"is_preprint":false},{"pmid":"42181174","id":"PMC_42181174","title":"Panx1 and P2X7R are associated with impaired skeletal health and delayed bone development in early onset of type 1 diabetes.","date":"2026","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/42181174","citation_count":0,"is_preprint":false},{"pmid":"24027825","id":"PMC_24027825","title":"[Distribution and regulation of Panx1 protein].","date":"2013","source":"Sheng li ke xue jin zhan [Progress in physiology]","url":"https://pubmed.ncbi.nlm.nih.gov/24027825","citation_count":0,"is_preprint":false},{"pmid":"41775813","id":"PMC_41775813","title":"Abnormal elevated PANX1 expression hampers endometrial decidualization by upregulating extracellular ATP concentration in patients with recurrent implantation failure.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41775813","citation_count":0,"is_preprint":false},{"pmid":"41319607","id":"PMC_41319607","title":"Downregulation of intracellular ATP levels by PANX1 inhibits ovarian granulosa cell proliferation and mediates follicular dysplasia in elderly women.","date":"2025","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/41319607","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52100,"output_tokens":8130,"usd":0.139125,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17659,"output_tokens":7729,"usd":0.14076,"stage2_stop_reason":"end_turn"},"total_usd":0.279885,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Cortical spreading depression (CSD) causes neuronal PANX1 megachannel opening and subsequent caspase-1 activation, followed by HMGB1 release from neurons and NF-κB activation in astrocytes; pharmacological suppression of this cascade abolished CSD-induced trigeminovascular activation, dural mast cell degranulation, and headache.\",\n      \"method\": \"In vivo pharmacological blockade and genetic suppression in mouse model of cortical spreading depression; measurement of trigeminovascular activation, HMGB1 release, caspase-1 activity\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (pharmacological blockade, HMGB1 release assays, caspase-1 activation, trigeminovascular readouts), widely replicated in subsequent papers\",\n      \"pmids\": [\"23449592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PANX1 forms a pore complex with P2X7 receptor; genetic loss of P2X7 or pharmacological inhibition of the P2X7-PANX1 pore complex suppresses spreading depolarization, reduces frequency and amplitude of depolarization events, and suppresses downstream neuroinflammatory gene expression (IL-1β, iNOS, COX-2) and trigeminovascular activation markers.\",\n      \"method\": \"Genetic knockout of P2x7, pharmacological pore complex inhibitors in wild-type mice and familial hemiplegic migraine mutant mice; electrophysiological thresholds, immunohistochemistry for inflammatory markers, CGRP/c-Fos expression\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological convergence across multiple readouts, replicated in multiple mouse models\",\n      \"pmids\": [\"28430869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Intracellular cysteine 346 of PANX1 is a critical regulatory residue; C346S mutation causes constitutively active (leaky) hemichannel activity and subsequent cell death, as demonstrated by increased dye uptake and electrophysiological profiling; mutations at other intracellular cysteines did not substantially alter channel properties.\",\n      \"method\": \"Site-directed mutagenesis of PANX1 cysteine residues; dye uptake assays and electrophysiology in Xenopus oocytes and N2A cells\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with two orthogonal functional assays (dye uptake + electrophysiology), single lab\",\n      \"pmids\": [\"20829356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The food dye FD&C Blue No. 1 (BB FCF) is a selective inhibitor of PANX1 channels with an IC50 of 0.27 µM, with no significant effect on P2X7R at concentrations up to 100 µM; the related dye FD&C Green No. 3 similarly selectively inhibited PANX1; oxidized ATP (a P2X7R antagonist) did not significantly inhibit PANX1 channels.\",\n      \"method\": \"Electrophysiological recordings and dye uptake assays in cells expressing PANX1 or P2X7R; dose-response pharmacology\",\n      \"journal\": \"Journal of General Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology and dye uptake with dose-response, selective pharmacological characterization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23589583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous PANX1 missense variant p.Arg217His results in loss-of-function of the channel (assessed by dye uptake, ATP release, and electrophysiology) without affecting glycosylation or cell surface trafficking; the variant is not dominant-negative when co-expressed with wild-type PANX1; homozygosity causes multisystem dysfunction including intellectual disability, sensorineural hearing loss, skeletal defects, and primary ovarian failure.\",\n      \"method\": \"Whole exome sequencing; expression in HeLa, N2A, HEK293T, Ad293 cells; dye uptake, ATP release assays, electrophysiology; co-expression with wild-type PANX1\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three orthogonal functional assays (dye uptake, ATP release, electrophysiology) with trafficking controls, single lab\",\n      \"pmids\": [\"27129271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PANX1 channels make no detectable contribution to the P2X2 receptor I2 (dilated permeability) state; the I2 state is an intrinsic P2X2 property correlated with conformational changes in the cytosolic domain rather than Panx1 opening.\",\n      \"method\": \"Patch-clamp coordinated spectroscopy; tetracysteine tag/biarsenical fluorophore conformational assay; dye permeability measurements; Panx1 knockdown/inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — negative finding established by multiple orthogonal methods including novel conformational spectroscopy; mechanistically informative negative result\",\n      \"pmids\": [\"18689682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Endogenous PANX1 interacts with actin in neural stem/progenitor cells (NSC/NPCs) and also with actin-related protein 3 (Arp3); PANX1 plays roles in NSC/NPC migration and neurite extension associated with cytoskeletal dynamics.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins; scratch wound and neurite extension assays; Panx1 knockdown in VZ NSC/NPCs\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — endogenous Co-IP identifying two binding partners (actin and Arp3), functional assays with knockdown, single lab\",\n      \"pmids\": [\"23964896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PANX1 controls cellular properties of keratinocytes and dermal fibroblasts; Panx1 KO fibroblasts show increased proliferation, reduced collagen gel contraction comparable to probenecid-treated WT fibroblasts, and fail to upregulate α-smooth muscle actin in response to TGF-β (a marker of myofibroblast differentiation); Panx1 KO keratinocytes are more migratory; Panx1 KO mice show delayed wound healing and altered skin thickness.\",\n      \"method\": \"Panx1 KO mouse model; histology; scratch wound assays; proliferation assays; collagen gel contraction; TGF-β stimulation; pharmacological blockade with probenecid\",\n      \"journal\": \"Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO combined with pharmacological validation (probenecid), multiple cell-type specific phenotypic readouts, single lab\",\n      \"pmids\": [\"24522432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P2X7R and PANX1 are co-expressed in osteocytes and together form a major pathway for flow-induced ATP release in bone mechanosignaling; high glucose conditions (simulating type 1 diabetes) blunt P2X7R- and flow-induced Ca2+ signaling and ATP release from osteocytes, associated with altered P2X7R and PANX1 expression.\",\n      \"method\": \"Western blot for co-expression; oscillatory fluid shear stress assays; Ca2+ response measurements; ATP release measurements; diabetic mouse model (Akita); high glucose cell culture\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-expression established, functional ATP release and Ca2+ signaling assays, both in vitro and in vivo, single lab\",\n      \"pmids\": [\"27159053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PANX1 channels in microglia release purines that activate microglial P2RY12 receptors; P2RY12 signaling regulates capillary-associated microglia (CAM) interactions with brain capillaries; PANX1-/- and P2RY12-/- mice show capillary dilation, increased blood flow, and impaired vasodilation, phenocopying microglial depletion.\",\n      \"method\": \"PANX1-/- and P2RY12-/- mouse models; microglial depletion; morphological/ultrastructural analysis; blood flow measurements; pharmacological assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — convergent genetic evidence from two KO lines plus microglial depletion, multiple vascular readouts, establishes PANX1-P2RY12 coupling mechanism\",\n      \"pmids\": [\"34489419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TLR2 activation in macrophages by danger signals from necrotic tubular epithelial cells activates PANX1 channels via caspase-5, leading to ATP secretion through PANX1 and subsequent NLRP3 inflammasome activation; this TLR2/caspase-5/Panx1 axis drives necroinflammation in acute kidney injury.\",\n      \"method\": \"Conditioned medium from necrotic TECs applied to macrophages; siRNA knockdown of Panx1, TLR2, caspase-5; NLRP3 inflammasome activation assays; ATP measurement\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown of three pathway components with defined phenotypic readout, single lab\",\n      \"pmids\": [\"35473933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TNFα promotes PANX1 cleavage via a caspase 8/3-dependent pathway in colorectal cancer cells, enhancing ATP release; this ATP release through PANX1 activates P2RX7 receptor-mediated antitumor immunity, including dendritic cell maturation and T-cell activation during chemotherapy-induced immunogenic cell death.\",\n      \"method\": \"PANX1 cleavage assay; caspase inhibitor experiments; ATP release measurements; immune cell activation assays in vitro and in vivo; P2RX7 blockade\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (caspase pathway, ATP release, immune activation) with pharmacological blockade, single lab\",\n      \"pmids\": [\"38195677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PANX1 in polarized MDCK cells is preferentially delivered to the apical membrane domain; the cell-surface targeting domain maps to residues 307–379; a Y308F mutation (disrupting a putative YxxΦ basolateral sorting motif) or a Δ379 truncation causes MDCK cells to lose cell-cell contacts and polarization capacity, switching to a fibroblast-like phenotype.\",\n      \"method\": \"GFP-tagged Panx1 in polarized MDCK cells and BICR-M1Rk cells; domain deletion and point mutagenesis; live-cell imaging; immunofluorescence; spheroid culture\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with localization and phenotypic readouts, single lab, multiple constructs tested\",\n      \"pmids\": [\"31102595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PANX1-mediated ATP release is required for FAM3A's suppression of hepatic gluconeogenesis and lipogenesis; mechanistically, PANX1-released ATP activates P2Y receptors to inhibit gluconeogenesis via the Akt-FOXO1 pathway; PANX1-released ATP also activates calmodulin (CaM), which interacts with JNK to inhibit AP1 transcription factor and repress FAS expression and lipogenesis; FAM3A stimulates PANX1 expression via HSF1; FAM3A overexpression fails to suppress gluconeogenesis/lipogenesis in PANX1-deficient hepatocytes.\",\n      \"method\": \"Co-immunoprecipitation with MS; PANX1 global KO mice; adenovirus/AAV gene overexpression/knockdown in vivo; OGTT, PTT, ITT metabolic tests; ATP release measurements; Western blot\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS to identify interactions, genetic KO rescue experiments, multiple metabolic phenotype readouts, single lab\",\n      \"pmids\": [\"38937853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Non-ionotropic NMDA receptor (niNMDAR) signaling activates PANX1 via Src kinase; PANX1 releases ATP (but is not permeable to Ca2+) to activate P2X4 purinergic receptors, producing long-term depression (LTD) at CA3-CA1 hippocampal synapses following low-frequency stimulation.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in rat hippocampal slices; competitive NMDAR antagonist (MK-801) applied transiently vs continuously; pharmacological blockade of Panx1 (with rescue by exogenous ATP); P2X4 antagonist (5-BDBD); Src kinase inhibitors\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with multiple pharmacological dissection, ATP rescue experiment, single lab\",\n      \"pmids\": [\"39709529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Both astrocyte and neuronal PANX1 are required for long-term spatial reference memory but not spatial working memory in mice; global Panx1 deletion attenuates LTP and LTD at Schaffer collateral-CA1 synapses without altering basal synaptic transmission or paired-pulse facilitation.\",\n      \"method\": \"Global and cell-type specific Panx1 transgenic KO mice; 8-arm radial maze; hippocampal slice field potential recordings; LTP and LTD induction protocols\",\n      \"journal\": \"ASN Neuro\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection using cell-type specific KO combined with behavioral and electrophysiological readouts, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37365910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous PANX1 missense variants (p.Ser238Pro and p.Arg300Gln) alter PANX1 glycosylation pattern in cultured cells, cause aberrant PANX1 channel activation, and result in mouse oocyte death after in vitro fertilization; these variants follow autosomal recessive inheritance and cause female infertility.\",\n      \"method\": \"Whole exome sequencing; Western blot for glycosylation; electrophysiology and dye uptake for channel function; in vitro fertilization mouse oocyte assay\",\n      \"journal\": \"European Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — variant characterization using glycosylation, electrophysiology, and in vivo oocyte model, single lab\",\n      \"pmids\": [\"33495594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structural analysis reveals that PANX1 channel permeation selectivity is controlled by structural plasticity at the extracellular entrance formed by seven W74 residues; W74 side chains sample conformations from a constricted state permissive to chloride only, to a dilated state compatible with ATP; these states are coupled to variable cation-π interactions between W74 and R75; mefloquine acts as a positive modulator binding near the side tunnel to enhance ion flow.\",\n      \"method\": \"Cryo-EM structure determination; molecular dynamics/conformational analysis; mutagenesis (W74, R75); electrophysiology with mefloquine\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with mutagenesis and electrophysiological validation, defining structural basis of permeation and modulation, single lab\",\n      \"pmids\": [\"41381453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A metastasis-associated N-terminal truncation mutant Panx1(1-89) forms a constitutively active membrane channel capable of releasing ATP independently of full-length PANX1; basic structure-function features of the channel pore are conserved; elevated extracellular K+ enhances Panx1(1-89)-mediated conductance; the truncated channel retains sensitivity to most full-length PANX1 inhibitors.\",\n      \"method\": \"Electrophysiology; ATP release assays; pharmacological inhibitor profiling; extracellular K+ stimulation experiments in cells expressing Panx1(1-89)\",\n      \"journal\": \"FEBS Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology and ATP release with multiple inhibitor tests, single lab\",\n      \"pmids\": [\"40087867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATP stimulates macropinocytosis in Neuro2a neuroblastoma cells, driving cell size increase and PANX1 internalization to macropinosomes; mutation of extracellular tryptophan W74 in PANX1 abolishes ATP-evoked cell area enlargement; ARF6(Q67L) expression phenocopies ATP-induced PANX1 internalization; PI3K inhibition, actin disruption, and GTPase inhibition abolish ATP-induced PANX1 internalization.\",\n      \"method\": \"Cell area measurement; fluorescent PANX1 constructs; W74 mutagenesis; ARF6 Q67L expression; pharmacological inhibitors of PI3K, actin polymerization; co-localization with macropinosomal cargo\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with multiple inhibitor approaches and compartment co-localization, single lab\",\n      \"pmids\": [\"41250870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Raptinal simultaneously induces apoptosis and inhibits caspase-activated PANX1 via a mechanism distinct from carbenoxolone and trovafloxacin; PANX1 inhibition by raptinal suppresses ATP 'find-me' signal release, formation of apoptotic cell-derived extracellular vesicles, and NLRP3 inflammasome activation.\",\n      \"method\": \"Biochemical, cell biological, and electrophysiological approaches; caspase activation assays; PANX1 cleavage assays; ATP release; extracellular vesicle quantification; NLRP3 inflammasome assay; comparison with known inhibitors\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, biochemistry, functional assays), single lab\",\n      \"pmids\": [\"38336804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PANX1 deletion in cardiomyocytes increases glycolytic metabolism and glycolytic ATP production with concurrent decrease in oxidative phosphorylation; isoproterenol treatment of cardiomyocytes induces PANX1-dependent ATP release and Yo-Pro-1 uptake; cardiomyocyte-specific Panx1 KO mice are protected from isoproterenol-induced cardiac hypertrophy and show decreased immune cell (particularly neutrophil) recruitment to myocardium.\",\n      \"method\": \"Cardiomyocyte-specific Panx1 KO mouse (Panx1MyHC6); metabolic flux analysis in vivo and in vitro; isoproterenol treatment; spironolactone and siRNA-mediated PANX1 blockade; Yo-Pro-1 uptake; flow cytometry for immune cells\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific genetic KO with pharmacological and siRNA validation, multiple orthogonal metabolic and immune readouts, single lab\",\n      \"pmids\": [\"38957990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human and mouse PANX1 orthologs differ in activation mechanisms: human PANX1 is insensitive to stimulation with high extracellular [K+] but responds to P2X7 receptor activation, while mouse PANX1 responds to both stimuli; human PANX1 polymorphism Q5H (rs1138800) is a gain-of-function and E390D (rs74549886) is a loss-of-function variant for P2X7-mediated channel activation.\",\n      \"method\": \"Dye uptake and electrophysiology in N2a neuroblastoma cells expressing endogenous mPanx1 or exogenous hPanx1; human PANX1 polymorphic variants expressed in Panx1-null cells; high K+ stimulation; P2X7 receptor activation\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology and dye uptake with multiple variants and stimuli, single lab\",\n      \"pmids\": [\"38100403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cholesterol depletion (by methyl-β-cyclodextrin) and inhibition of cholesterol synthesis (lovastatin) decrease lateral diffusion of PANX1 in the plasma membrane (assessed by FRAP) while enhancing PANX1 channel activity (dye uptake, ATP release, ionic current) in cholesterol-depleted astrocytes and PANX1-transfected cells.\",\n      \"method\": \"FRAP for membrane mobility; electrophysiology; dye uptake; ATP release assays; pharmacological cholesterol manipulation in astrocytes and transfected cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP localization linked to function via multiple activity assays, single lab\",\n      \"pmids\": [\"36291086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, Panx1a and Panx1b (both homologous to human PANX1) exert dual pro- and anti-seizure activities via ATP release and P2rx7 receptor signaling; loss of Panx1a function reduces ictal-like events and seizure-like locomotion induced by pentylenetetrazol; transcriptome profiling reveals distinct metabolic and cell-signaling states associated with loss of Panx1a.\",\n      \"method\": \"Genetic KO (panx1a-/-) and pharmacological blockade of Panx1a/Panx1b in zebrafish larvae; electrophysiology; behavioral analysis; RNA-seq; ATP release measurements\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent genetic and pharmacological evidence in zebrafish with electrophysiological and transcriptomic readouts, single lab\",\n      \"pmids\": [\"35585187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"cAMP-mediated pathway does NOT drive ATP release from red blood cells (RBCs) through PANX1; Panx1-/- mice show no decrease in exercise performance; treatment with stable cAMP analog does not induce ATP release from WT or Panx1-/- RBCs; multiple pharmacological AC activators increase intracellular cAMP but do not induce ATP release.\",\n      \"method\": \"Panx1-/- mouse model; exercise performance testing; RBC ex vivo ATP release assays; cAMP measurement by mass spectrometry; pharmacological adenylate cyclase activation\",\n      \"journal\": \"American Journal of Physiology - Cell Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistically informative negative finding using genetic KO plus multiple pharmacological tools with quantitative cAMP measurement, single lab\",\n      \"pmids\": [\"28855161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neuronal PANX1 drives peripheral sensitization in inflammatory pain through cell-autonomous effects on neuronal excitability; neuron-specific Panx1 KO reduces pain sensitivity after CFA-induced inflammation; neuronal Panx1 enhances DRG neuron response to ATP; Panx1 supports Wnt/β-catenin-dependent DRG neurogenesis; ATP release from Panx1 channels increases Ca2+ responses in DRGNs and satellite glial cells.\",\n      \"method\": \"Global and neuron-specific Panx1 KO mice; von Frey test after CFA injection; confocal microscopy; Sholl analysis; electrophysiology in Neuro2a and DRG neurons; ethidium bromide dye uptake; calcium imaging; β-galactosidase staining in transgenic mice\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific genetic KO with multiple orthogonal mechanistic assays (electrophysiology, Ca2+ imaging, dye uptake, neurogenesis markers), single lab\",\n      \"pmids\": [\"38685116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PANX1 variants (p.Ser137Leu and p.Asn326del) alter PANX1 glycosylation, cause aberrant channel activation, affect ATP release and membrane electrophysiological properties, and result in human and mouse oocyte death in vitro; both variants follow autosomal dominant inheritance.\",\n      \"method\": \"Whole exome sequencing; Western blot for glycosylation; ATP release measurement; electrophysiology; in vitro mouse and human oocyte fertilization assay\",\n      \"journal\": \"Journal of Ovarian Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (glycosylation, electrophysiology, ATP release) validated with human oocyte data, single lab\",\n      \"pmids\": [\"39232764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGM2 interacts with PANX1 (co-immunoprecipitation); TGM2-PANX1 interaction promotes lipid deposition; knockdown or pharmacological inhibition of PANX1 decreases levels of PPARα and PANK1 induced by adriamycin, suggesting PANX1 operates downstream of TGM2 in a pathway regulating lipid metabolism.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown of PANX1; Western blot for PPARα and PANK1; adriamycin nephropathy cell and mouse model; YR-7 peptide treatment\",\n      \"journal\": \"Translational Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying TGM2-PANX1 interaction, downstream pathway placement based on knockdown with one cell model, single lab\",\n      \"pmids\": [\"38734063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PANX1 channel activity is required for endometrial decidualization: PANX1 overexpression in human endometrial stromal cells (HESCs) increases extracellular ATP and impairs decidualization markers (PRL, IGFBP-1) and cytoskeletal morphology; PANX1 knockdown also impairs decidualization, indicating that normal PANX1 expression level is required; this mechanism is associated with recurrent implantation failure.\",\n      \"method\": \"PANX1 plasmid overexpression and siRNA knockdown in HESCs; extracellular ATP detection; Western blot for PRL and IGFBP-1; immunofluorescence for cytoskeleton; animal model validation\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with functional decidualization readouts and in vivo validation, single lab\",\n      \"pmids\": [\"41775813\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PANX1 is a large-pore ATP release channel whose gating is structurally controlled by conformational flexibility at extracellular W74 residues (cryo-EM), regulated by intracellular C346, and activated downstream of P2X7 receptor, Src kinase, caspase cleavage, and mechanical stimuli; it forms functional complexes with P2X7R and signals through released ATP to P2RY12 and P2X4 receptors, driving diverse processes including neuroinflammation (via caspase-1/HMGB1 in cortical spreading depression), synaptic plasticity (LTP/LTD), pain sensitization, oocyte development, cardiac metabolism and hypertrophy, immune cell recruitment, and skin/mammary tissue homeostasis, while pathogenic gain- or loss-of-function PANX1 variants disrupt glycosylation and channel activity to cause human disease including female infertility and multisystem disorders.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PANX1 is a large-pore plasma membrane channel that mediates regulated release of ATP, coupling diverse cellular stimuli to purinergic signaling across the nervous, immune, metabolic, and reproductive systems [#0, #14, #21]. Cryo-EM defines the structural basis of its permeation: an extracellular constriction formed by seven W74 residues samples conformations ranging from a chloride-only state to a dilated, ATP-permeant state, with cation-\\u03c0 interactions between W74 and R75 controlling selectivity and the antimalarial mefloquine acting as a positive modulator [#17]. Channel gating is further controlled by an intracellular regulatory cysteine (C346), whose mutation produces a constitutively leaky, cytotoxic channel [#2]. PANX1 is activated through multiple convergent routes\\u2014physical and functional coupling to the P2X7 receptor [#1, #22], Src kinase downstream of non-ionotropic NMDA receptors [#14], and caspase-dependent cleavage (caspase-1, caspase-5, caspase-8/3, and an N-terminal truncation that yields a constitutively active fragment) [#10, #11, #18]\\u2014and the released ATP signals onward to purinergic receptors including P2RY12, P2X4, and P2X7 [#9, #14, #11]. Through this ATP-release function PANX1 drives neuroinflammation in cortical spreading depression via a caspase-1/HMGB1 cascade [#0], hippocampal LTP and LTD underlying spatial memory [#14, #15], peripheral pain sensitization [#26], cardiomyocyte metabolism and isoproterenol-induced hypertrophy [#21], inflammasome-dependent injury responses [#10, #20], and tissue homeostasis in skin, bone, and the endometrium [#7, #8, #29]. Homozygous and dominant PANX1 variants that disrupt glycosylation and cause aberrant channel activation produce female infertility through oocyte death, and a loss-of-function variant causes a multisystem disorder with intellectual disability, sensorineural hearing loss, skeletal defects, and primary ovarian failure [#4, #16, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that PANX1 is not responsible for the P2X2 receptor dilated-permeability (I2) state, distinguishing intrinsic receptor conformational change from pannexin channel opening and constraining how PANX1 is invoked in purinergic permeability.\",\n      \"evidence\": \"Patch-clamp coordinated spectroscopy and conformational fluorophore assays with Panx1 knockdown\",\n      \"pmids\": [\"18689682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address PANX1 coupling to other P2X subtypes\", \"Negative result for one receptor only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified intracellular cysteine 346 as a critical gating residue, showing PANX1 channel opening is tightly regulated and that loss of this control produces a leaky, lethal channel.\",\n      \"evidence\": \"Site-directed mutagenesis with dye uptake and electrophysiology in Xenopus oocytes and N2A cells\",\n      \"pmids\": [\"20829356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological modification controlling C346 not defined\", \"No structural model of the closed state\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked neuronal PANX1 megachannel opening to a defined neuroinflammatory cascade (caspase-1/HMGB1/NF-\\u03baB) driving headache, establishing PANX1 as an upstream trigger of trigeminovascular activation.\",\n      \"evidence\": \"In vivo pharmacological blockade and genetic suppression in a mouse cortical spreading depression model\",\n      \"pmids\": [\"23449592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus coupling PANX1 to caspase-1 not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided a selective small-molecule tool (BB FCF) distinguishing PANX1 from P2X7R pharmacologically, enabling clean dissection of PANX1-specific contributions.\",\n      \"evidence\": \"Dose-response electrophysiology and dye uptake in PANX1- vs P2X7R-expressing cells\",\n      \"pmids\": [\"23589583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo selectivity and potency not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected PANX1 to cytoskeletal machinery by demonstrating endogenous interaction with actin and Arp3 and roles in neural progenitor migration, hinting at channel-independent or cytoskeleton-coupled functions.\",\n      \"evidence\": \"Endogenous co-immunoprecipitation with scratch-wound and neurite assays under Panx1 knockdown\",\n      \"pmids\": [\"23964896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect actin/Arp3 binding not resolved\", \"Whether migration phenotype depends on channel activity unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a homeostatic role for PANX1 in skin, regulating fibroblast contraction, myofibroblast differentiation, keratinocyte migration, and wound healing.\",\n      \"evidence\": \"Panx1 KO mice and probenecid blockade with proliferation, collagen contraction, and TGF-\\u03b2 assays\",\n      \"pmids\": [\"24522432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream purinergic receptor in skin not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a human loss-of-function PANX1 variant (R217H) causing a multisystem disorder, providing the first direct gene-disease link and showing the channel defect is recessive and trafficking-independent.\",\n      \"evidence\": \"Whole exome sequencing with dye uptake, ATP release, electrophysiology, and trafficking controls\",\n      \"pmids\": [\"27129271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific basis of each multisystem phenotype not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed P2X7R-PANX1 co-expression mediates flow-induced ATP release in osteocyte mechanosignaling, extending PANX1 to bone and showing hyperglycemia blunts this pathway.\",\n      \"evidence\": \"Western blot co-expression, fluid shear stress, Ca2+ and ATP assays in a diabetic mouse model\",\n      \"pmids\": [\"27159053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical PANX1-P2X7 complex in osteocytes not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated PANX1 forms a functional pore complex with P2X7R that drives spreading depolarization and neuroinflammation, mechanistically linking the two channels.\",\n      \"evidence\": \"P2x7 knockout and pore-complex inhibitors in wild-type and familial hemiplegic migraine mutant mice\",\n      \"pmids\": [\"28430869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural interface of the complex not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Excluded a cAMP-PANX1 pathway for ATP release from red blood cells, refining the contexts in which PANX1 mediates ATP efflux.\",\n      \"evidence\": \"Panx1-/- mice, exercise testing, RBC ATP release, and cAMP mass spectrometry with AC activators\",\n      \"pmids\": [\"28855161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not rule out PANX1 ATP release via other RBC stimuli\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped a C-terminal surface-targeting domain (307\\u2013379) and a Yxx\\u03a6 sorting motif controlling apical PANX1 delivery and epithelial polarity, linking PANX1 trafficking to cell-cell contact maintenance.\",\n      \"evidence\": \"GFP-PANX1 domain deletion and Y308F mutagenesis in polarized MDCK cells with imaging\",\n      \"pmids\": [\"31102595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether polarity phenotype requires channel activity unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PANX1-P2RY12 coupling in microglia controlling capillary interactions and cerebral blood flow, defining a discrete neurovascular signaling axis.\",\n      \"evidence\": \"PANX1-/- and P2RY12-/- mice, microglial depletion, and blood flow measurements\",\n      \"pmids\": [\"34489419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific purine released and its receptor binding kinetics not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified recessive PANX1 variants (S238P, R300Q) that alter glycosylation and cause aberrant activation leading to oocyte death and female infertility, establishing PANX1 in reproduction.\",\n      \"evidence\": \"Whole exome sequencing, glycosylation Western blot, electrophysiology, and IVF oocyte assays\",\n      \"pmids\": [\"33495594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between altered glycosylation and oocyte death not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed species-specific PANX1 activation\\u2014human PANX1 responds to P2X7 but not high K+\\u2014and human polymorphisms (Q5H gain-, E390D loss-of-function), clarifying translational caveats and natural functional variation.\",\n      \"evidence\": \"Dye uptake and electrophysiology comparing mouse and human PANX1 and polymorphic variants in Panx1-null cells\",\n      \"pmids\": [\"38100403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of species difference in K+ sensitivity not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked plasma membrane cholesterol to PANX1 lateral mobility and activity, showing cholesterol depletion enhances channel function while reducing diffusion.\",\n      \"evidence\": \"FRAP, electrophysiology, dye uptake, and ATP release with cholesterol manipulation in astrocytes\",\n      \"pmids\": [\"36291086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cholesterol binds PANX1 directly unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PANX1 orthologs exert dual pro- and anti-seizure roles via ATP/P2rx7 signaling in zebrafish, broadening understanding of PANX1 in excitability.\",\n      \"evidence\": \"panx1a-/- and pharmacological blockade in zebrafish larvae with electrophysiology, behavior, and RNA-seq\",\n      \"pmids\": [\"35585187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling opposing pro/anti-seizure effects not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a TLR2/caspase-5/PANX1 axis in macrophages connecting necrotic cell danger signals to ATP secretion and NLRP3 inflammasome activation in kidney injury.\",\n      \"evidence\": \"Conditioned medium from necrotic tubular cells with siRNA knockdown of Panx1, TLR2, caspase-5\",\n      \"pmids\": [\"35473933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct caspase-5 cleavage site on PANX1 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated both neuronal and astrocytic PANX1 are required for hippocampal LTP/LTD and long-term spatial memory, establishing a cognitive role for the channel.\",\n      \"evidence\": \"Global and cell-type specific Panx1 KO mice with radial maze and field potential recordings\",\n      \"pmids\": [\"37365910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between PANX1 ATP release and plasticity machinery not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved a niNMDAR\\u2192Src\\u2192PANX1\\u2192ATP\\u2192P2X4 pathway producing hippocampal LTD, defining a precise signaling chain for PANX1 in synaptic depression.\",\n      \"evidence\": \"Patch-clamp in hippocampal slices with NMDAR, Src, PANX1, and P2X4 pharmacology plus ATP rescue\",\n      \"pmids\": [\"39709529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Src activation gates PANX1 structurally not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed neuronal PANX1 drives inflammatory pain cell-autonomously by enhancing DRG excitability and supporting Wnt/\\u03b2-catenin neurogenesis, placing PANX1 in peripheral sensitization.\",\n      \"evidence\": \"Global and neuron-specific Panx1 KO mice with von Frey, electrophysiology, Ca2+ imaging, and neurogenesis markers\",\n      \"pmids\": [\"38685116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of channel ATP release vs neurogenesis to pain not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a cardiomyocyte metabolic and immune role for PANX1, with deletion shifting metabolism toward glycolysis and protecting against isoproterenol-induced hypertrophy and neutrophil recruitment.\",\n      \"evidence\": \"Cardiomyocyte-specific Panx1 KO mice with metabolic flux, Yo-Pro-1 uptake, and flow cytometry\",\n      \"pmids\": [\"38957990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PANX1 ATP release to metabolic substrate switching not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a TNF\\u03b1\\u2192caspase-8/3\\u2192PANX1 cleavage pathway enhancing ATP release that activates P2RX7-mediated antitumor immunity during immunogenic cell death.\",\n      \"evidence\": \"PANX1 cleavage and ATP release assays with caspase inhibitors and immune activation readouts in colorectal cancer models\",\n      \"pmids\": [\"38195677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution to clinical immunotherapy response not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PANX1 ATP release downstream of FAM3A to suppress hepatic gluconeogenesis (P2Y/Akt-FOXO1) and lipogenesis (CaM/JNK/AP1), defining a hepatic metabolic signaling node.\",\n      \"evidence\": \"Co-IP/MS, global Panx1 KO and rescue, and in vivo metabolic testing\",\n      \"pmids\": [\"38937853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs autocrine purinergic step in hepatocytes not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a narrow expression window for PANX1 in endometrial decidualization, with both overexpression and knockdown impairing decidualization markers, linking PANX1 to implantation failure.\",\n      \"evidence\": \"Bidirectional PANX1 manipulation in human endometrial stromal cells with decidualization markers and ATP measurement\",\n      \"pmids\": [\"41775813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream purinergic receptor in endometrium not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified raptinal as an inhibitor of caspase-activated PANX1 acting by a distinct mechanism, suppressing apoptotic 'find-me' ATP signals, extracellular vesicle formation, and NLRP3 activation.\",\n      \"evidence\": \"Electrophysiology, biochemistry, ATP release, EV quantification, and NLRP3 assays versus known inhibitors\",\n      \"pmids\": [\"38336804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site of raptinal on PANX1 not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified dominant PANX1 variants (S137L, N326del) altering glycosylation and channel activation that cause oocyte death and infertility, expanding the inheritance modes of PANX1 reproductive disease.\",\n      \"evidence\": \"Whole exome sequencing with glycosylation, electrophysiology, ATP release, and human/mouse oocyte IVF assays\",\n      \"pmids\": [\"39232764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant mechanism (gain-of-function vs dominant-negative) not formally resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed PANX1 acts downstream of TGM2 to promote lipid deposition in nephropathy, placing PANX1 in a renal lipid metabolism pathway.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and PPAR\\u03b1/PANK1 Western blot in adriamycin nephropathy models\",\n      \"pmids\": [\"38734063\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Pathway placement from one cell model only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the structural basis of PANX1 permeation selectivity at near-atomic resolution, showing W74 conformational plasticity and W74-R75 cation-\\u03c0 interactions gate the channel between chloride-only and ATP-permeant states, with mefloquine as a positive modulator.\",\n      \"evidence\": \"Cryo-EM structure determination with conformational analysis, W74/R75 mutagenesis, and mefloquine electrophysiology\",\n      \"pmids\": [\"41381453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How upstream activators (P2X7, Src, caspase) drive W74 conformational change not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed an N-terminal truncation mutant Panx1(1-89) forms a constitutively active, K+-enhanced ATP-releasing channel that retains inhibitor sensitivity, linking PANX1 fragments to metastasis.\",\n      \"evidence\": \"Electrophysiology, ATP release, inhibitor profiling, and high-K+ stimulation of Panx1(1-89)-expressing cells\",\n      \"pmids\": [\"40087867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo generation and metastatic mechanism of the truncation not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated ATP-driven macropinocytosis internalizes PANX1 via a W74-, ARF6-, PI3K-, and actin-dependent route, revealing feedback regulation of channel surface levels.\",\n      \"evidence\": \"Cell area measurement, W74 mutagenesis, ARF6(Q67L) expression, and PI3K/actin/GTPase inhibitors with macropinosome co-localization in Neuro2a cells\",\n      \"pmids\": [\"41250870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger and consequence of PANX1 internalization in vivo unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct upstream activators (P2X7 complex formation, Src phosphorylation, caspase cleavage, mechanical and lipid-environment cues) converge to drive the W74/R75 conformational transition that opens the ATP-permeant pore remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of an activated, P2X7-bound or Src-phosphorylated PANX1\", \"Coupling between cleavage events and the W74 gate not mapped\", \"How glycosylation status biochemically controls gating unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 4, 17, 18, 22]},\n      {\"term_id\": \"GO:0022836\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 12, 17, 23]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 10, 11, 20]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [14, 15, 26]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 20]}\n    ],\n    \"complexes\": [\n      \"P2X7R-PANX1 pore complex\"\n    ],\n    \"partners\": [\n      \"P2RX7\",\n      \"ACTB\",\n      \"ACTR3\",\n      \"TGM2\",\n      \"FAM3A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}