{"gene":"PIEZO2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2010,"finding":"Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Overexpression of mouse Piezo2 in cells induced rapidly adapting mechanically activated currents; knockdown of Piezo2 in dorsal root ganglion neurons specifically reduced rapidly adapting MA currents.","method":"RNA interference knockdown, heterologous overexpression, electrophysiology (patch-clamp)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RNAi knockdown + overexpression + electrophysiology), replicated across cell types, foundational study","pmids":["20813920"],"is_preprint":false},{"year":2012,"finding":"Piezo2-mediated mechanically activated currents in sensory neurons are enhanced by bradykinin receptor beta 2 (BDKRB2) activation via PKA and PKC signaling; PKA and PKC agonists directly enhance piezo2 activity, and BDKRB2-mediated effects are abolished by PKA and PKC inhibitors.","method":"Heterologous expression, pharmacological activation/inhibition, patch-clamp electrophysiology in sensory neurons and HEK cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal pharmacological interventions plus electrophysiology in both native neurons and heterologous system, single lab","pmids":["22921401"],"is_preprint":false},{"year":2013,"finding":"PIEZO2 gain-of-function mutations (E2727del and I802F) affect channel inactivation kinetics: E2727del slows inactivation and both mutations cause faster recovery from inactivation, resulting in increased channel activity in response to mechanical stimuli, linking PIEZO2 dysfunction to Distal Arthrogryposis Type 5.","method":"Electrophysiological characterization of mutant PIEZO2 expressed in cells (patch-clamp), whole-exome sequencing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological characterization of two independent disease mutations with defined biophysical mechanism, single lab","pmids":["23487782"],"is_preprint":false},{"year":2013,"finding":"Epac1 activation potentiates Piezo2-mediated mechanotransduction: the Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents via Piezo2 in a manner dependent on cytosolic calcium and cytoskeleton integrity, but independent of PKC or PKA; in vivo Piezo2 knockdown attenuates 8-pCPT-induced mechanical allodynia.","method":"Patch-clamp electrophysiology, pharmacological manipulation, in vivo knockdown, behavioral assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, pharmacology, in vivo knockdown, behavior), single lab","pmids":["23575686"],"is_preprint":false},{"year":2014,"finding":"Piezo2 is the Merkel-cell mechanotransduction channel: Merkel cells produce touch-sensitive currents in vitro that completely depend on Piezo2, as shown by skin-specific Piezo2 conditional knockout mice lacking Merkel-cell mechanosensitivity; loss also reduces slowly adapting in vivo firing rates and decreases behavioral responses to gentle touch.","method":"Conditional knockout mice (skin-specific), patch-clamp electrophysiology, in vivo nerve recordings, behavioral assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal phenotypic readouts (electrophysiology, in vivo recordings, behavior), replicated concept across labs","pmids":["24717433"],"is_preprint":false},{"year":2014,"finding":"Piezo2 is the major transducer for touch sensation: mice lacking Piezo2 in adult sensory neurons and Merkel cells exhibit profound loss of touch sensation; most rapidly adapting MA currents in DRG cultures are absent; mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2 in ex vivo skin-nerve preparations.","method":"Conditional knockout mice, patch-clamp electrophysiology in DRG cultures, ex vivo skin-nerve preparation electrophysiology, behavioral assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple independent assays (DRG electrophysiology, ex vivo nerve prep, behavior), replicated concept","pmids":["25471886"],"is_preprint":false},{"year":2014,"finding":"PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors: CRISPR/Cas9-mediated PIEZO2 gene deletion abolishes mechanosensitivity in hES cell-derived sensory neurons.","method":"CRISPR/Cas9 gene deletion, hES/hiPS cell differentiation protocol, patch-clamp electrophysiology","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic knockout with direct functional readout in human-derived neurons, single lab with rigorous controls","pmids":["25469543"],"is_preprint":false},{"year":2014,"finding":"Combined directed expression of Piezo1 and Piezo2 in chondrocytes produces potentiated mechanically induced Ca2+ signals and electrical currents compared with single-Piezo expression; Piezo1- or Piezo2-specific siRNA inhibits mechanically evoked Ca2+ transients in primary articular chondrocytes.","method":"Heterologous co-expression, siRNA knockdown, atomic force microscopy-induced Ca2+ imaging, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-expression and siRNA knockdown with Ca2+ imaging and electrophysiology, single lab","pmids":["25385580"],"is_preprint":false},{"year":2015,"finding":"Piezo2 is the principal mechanotransduction channel for proprioception: Piezo2 is expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs; two independent mouse lines lacking Piezo2 in proprioceptive neurons show severely uncoordinated movements, and stretch-induced firing of proprioceptors in muscle-nerve recordings is markedly reduced.","method":"Conditional knockout mice (two independent lines), immunohistochemistry, in vitro patch-clamp, muscle-nerve electrophysiology, behavioral analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO lines with multiple orthogonal assays (patch-clamp, muscle-nerve recordings, behavior)","pmids":["26551544"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function compound mutations in PIEZO2 in humans cause selective loss of discriminative touch perception and profoundly decreased proprioception, confirming PIEZO2 as a determinant of mechanosensation in humans; functional brain imaging and psychophysical testing established the selective sensory deficits.","method":"Whole-exome sequencing, in vitro functional assays, messenger RNA assays, functional brain imaging, psychophysical and kinematic testing","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — human genetic study with multiple orthogonal functional validation methods, single-center but rigorous","pmids":["27653382"],"is_preprint":false},{"year":2016,"finding":"Piezo2 in mesencephalic trigeminal nucleus proprioceptive neurons produces rapidly adapting mechanically activated currents that are fully dependent on Piezo2; selective deletion of Piezo2 in proprioceptors causes deficits in balance and coordination.","method":"Conditional knockout mice (proprioceptor-specific), patch-clamp electrophysiology, behavioral assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with electrophysiology and behavioral readout, single lab","pmids":["27184818"],"is_preprint":false},{"year":2016,"finding":"Mtmr2 (myotubularin related protein-2), a PI phosphatase, was identified as a native Piezo2 interactor in DRG; Mtmr2 attenuates Piezo2-mediated rapidly adapting MA currents through depletion of PI(3,5)P2; a PI(3,5)P2 binding region specific to Piezo2 (not Piezo1) confers sensitivity to Mtmr2 regulation.","method":"Mass spectrometry-based native interactomics, co-immunoprecipitation, patch-clamp electrophysiology, pharmacological inhibitors, domain-swapped Piezo2 mutant analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — native interactomics, functional electrophysiology, domain-swap mutagenesis, multiple orthogonal approaches, single lab","pmids":["29521261"],"is_preprint":false},{"year":2016,"finding":"Pericentrin, identified in a native Piezo2 interactomics screen of mouse DRG, modulates Piezo2 activity and membrane expression in somatosensory neurons.","method":"Mass spectrometry-based native interactomics, functional electrophysiology, membrane expression assay","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS interactomics followed by functional validation, single lab","pmids":["27345391"],"is_preprint":false},{"year":2017,"finding":"Piezo2 is extensively alternatively spliced, producing isoforms with distinct biophysical properties including differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics; splicing is cell-type specific even within sensory ganglia.","method":"RNA sequencing/isoform profiling, biophysical characterization of splice variants by patch-clamp electrophysiology","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiological characterization of multiple splice variants with multiple biophysical parameters, single lab, rigorous","pmids":["29212024"],"is_preprint":false},{"year":2017,"finding":"Channel inactivation is the molecular mechanism underlying frequency filtering of Piezo2 (and Piezo1) in response to repetitive mechanical stimuli; human disease-related point mutations that alter inactivation kinetics correspondingly alter frequency filtering.","method":"Patch-clamp electrophysiology of heterologously expressed channels, numerical simulations, disease-related point mutations","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology with mutagenesis and simulation, single lab, rigorous mechanistic analysis","pmids":["28636944"],"is_preprint":false},{"year":2017,"finding":"D-GsMTx4 (spider peptide) reversibly and dose-dependently inhibits Piezo2 mechanosensitive currents in response to mechanical force, acting on both potency and efficacy.","method":"Patch-clamp electrophysiology in HEK293 cells overexpressing human Piezo2, dose-response pharmacology","journal":"Channels (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct electrophysiology in heterologous system, single lab, single method","pmids":["28085630"],"is_preprint":false},{"year":2018,"finding":"Piezo2 channel-mediated Ca2+ influx activates RhoA in brain metastatic cancer cells, controlling formation and orientation of stress fibers and focal adhesions; mechanism involves Fyn kinase recruitment to the cell leading edge and calpain activation; YAP nuclear translocation and cancer invasion phenotypes depend on this Piezo2-RhoA axis.","method":"siRNA knockdown, Ca2+ imaging, RhoA activity assays, confocal microscopy, dominant-positive RhoA rescue experiments, invasion/migration assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockdown plus rescue with dominant-positive RhoA/mDia1, multiple orthogonal assays, single lab","pmids":["29432180"],"is_preprint":false},{"year":2018,"finding":"Piezo2 is the primary mechanotransducer in enterochromaffin cells: mechanical stimulation leads to Piezo2-dependent inward ionic currents, intracellular Ca2+ increase, and serotonin release; conditional knockout of intestinal epithelial Piezo2 significantly decreases mechanically stimulated epithelial secretion.","method":"Lineage tracing, super-resolution microscopy, patch-clamp electrophysiology, Ca2+ imaging in organoids, ELISA for serotonin, conditional knockout mice, siRNA knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, serotonin ELISA, conditional KO, siRNA) in multiple model systems","pmids":["30037999"],"is_preprint":false},{"year":2019,"finding":"Cold potentiates Piezo2-dependent mechanically activated currents in vertebrate mechanoreceptors; cold sensitivity of Piezo2 is dependent on its blade domains, which render the channel resistant to cold-induced perturbations of the plasma membrane physical properties; this is a distinct mechanism from Piezo1 cold sensitivity.","method":"Patch-clamp electrophysiology in mechanoreceptors and heterologous systems with Piezo2 orthologs, domain mutagenesis/swapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology with domain mutagenesis across species, single lab, rigorous","pmids":["31413193"],"is_preprint":false},{"year":2019,"finding":"Charged amino acids at the beam domain–CTD interface and hydrophobic interactions between Y2807 of the CTD and pore-lining helices are required for normal mechanosensitivity of PIEZO2; an intrinsically disordered domain adjacent to the beam acts as a cytosolic plug limiting ion permeation by clogging the inner vestibule.","method":"Site-directed mutagenesis, patch-clamp electrophysiology (single-channel and whole-cell recordings), structure-guided analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-guided mutagenesis with single-channel and whole-cell electrophysiology, mechanistic domain interface identified, single lab","pmids":["31235572"],"is_preprint":false},{"year":2019,"finding":"Piezo2 is a low-threshold, positive pressure-specific, curvature-sensitive, mechanically activated cation channel; single channel conductance is ~28.6 pS in Merkel cell carcinoma cells; positive pressure ≥5 mmHg activates Piezo2 while negative pressure does not (unlike Piezo1).","method":"Patch-clamp electrophysiology (cell-attached and whole-cell), step indentation and pressure application protocols","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct single-channel electrophysiology but single lab, single cell type","pmids":["31015490"],"is_preprint":false},{"year":2020,"finding":"PIEZO2 acts as a mechanosensor in both bladder urothelium and innervating sensory neurons; humans and mice lacking functional PIEZO2 have impaired bladder control and deficient bladder-filling sensation; PIEZO2 is required for low-threshold bladder-stretch sensing and urethral micturition reflexes.","method":"Conditional knockout mice (urothelial and neuron-specific), cystometry, behavioral bladder assessment, human genetic analysis with patient-reported outcomes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in two cell types plus human genetic validation with multiple functional readouts","pmids":["33057202"],"is_preprint":false},{"year":2020,"finding":"Gi-coupled receptor activation potentiates Piezo2 currents via Gβγ in a manner dependent on downstream PI3K and MAPK kinases; sumatriptan (Gi-coupled 5-HT1B/1D receptor agonist) increases mechanical sensitivity in mice, abolished by PI3K and MAPK inhibition; Piezo1 currents are inhibited (not potentiated) by the same pathway.","method":"Patch-clamp electrophysiology in DRG neurons and heterologous Piezo2 expression, pharmacological inhibitors, in vivo behavioral assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiology in native neurons and heterologous system, pharmacological dissection of pathway, in vivo behavioral validation, single lab","pmids":["32227462"],"is_preprint":false},{"year":2020,"finding":"Nedd4-2 interacts with Piezo2 (co-immunoprecipitation) and inhibits Piezo2 MA currents in co-expressed HEK293T cells; Nedd4-2 upregulation in baroreceptor nodose ganglia neurons of hypertensive rats leads to downregulation of Piezo2, reducing RA-MA currents and impairing baroreflex.","method":"Co-immunoprecipitation, patch-clamp electrophysiology in HEK293T cells, siRNA knockdown in vivo, blood pressure measurement, spontaneously hypertensive rat model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP plus functional electrophysiology, in vivo KD with blood pressure phenotype, single lab","pmids":["33352230"],"is_preprint":false},{"year":2021,"finding":"Urothelial PIEZO2 (expressed in a subset of umbrella cells) is required for normal voiding function; male Piezo2-KO mice exhibit urinary incontinence; dual Piezo1/2-KO mice show decreased urothelial mechanical responses, diminished ATP release, and bladder hypoactivity.","method":"Conditional urothelial KO mice (Piezo2, Piezo1, dual), voiding behavior monitoring, urothelial mechanosensitivity assays, ATP release measurement","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with multiple functional readouts (ATP release, bladder activity, behavior), replicates and extends PMID 33057202","pmids":["34464353"],"is_preprint":false},{"year":2021,"finding":"PIEZO2 mediates ultrasonic hearing via cochlear outer hair cells: knockout of PIEZO2 in outer hair cells (OHCs) specifically abolishes associative learning during ultrasonic frequency exposure; ultrasonic Ca2+ transduction in cochlea requires both PIEZO2 and the conventional hair-cell mechanotransduction channel.","method":"Cell-type-specific knockout mice, audiometry, acoustically associative freezing behavior, ex vivo cochlear Ca2+ imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with multiple orthogonal readouts (audiometry, behavior, Ca2+ imaging), single lab","pmids":["34244441"],"is_preprint":false},{"year":2022,"finding":"The intrinsically disordered linker IDR5 (between transmembrane helices 12 and 13) is required for activation of PIEZO2 by cytoskeleton-transmitted forces; IDR5 deletion abolishes PIEZO2-mediated inhibition of neurite outgrowth and partially reduces cell indentation sensitivity but does not alter stretch sensitivity, indicating PIEZO2 detects different mechanical stimuli via different force transmission pathways.","method":"Site-directed mutagenesis/deletion, patch-clamp electrophysiology (poking and stretch), neurite outgrowth assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with multiple functional assays distinguishing force transmission pathways, single lab","pmids":["35292651"],"is_preprint":false},{"year":2022,"finding":"TMEM120A coexpression decreases the amplitudes of mechanically activated PIEZO2 currents and increases their activation threshold; TMEM120A does not inhibit PIEZO1 or TREK1; siRNA knockdown of Tmem120a in DRG neurons increases rapidly adapting MA current amplitudes and decreases thresholds.","method":"Heterologous co-expression, patch-clamp electrophysiology, siRNA knockdown in DRG neurons","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct electrophysiology in heterologous and native neuron systems with both overexpression and knockdown, single lab","pmids":["35819364"],"is_preprint":false},{"year":2022,"finding":"PKA-dependent modulation of PIEZO2 requires a combination of nine putative PKA phosphorylation sites on four different intracellular disordered regions; mutation of all nine sites abolishes PKA-induced sensitization; PKA modulates PIEZO2 responses to cell indentation but not to pressure-induced membrane stretch, suggesting polymodal mechanosensing through different domains.","method":"Phosphorylation site prediction, site-directed mutagenesis, patch-clamp electrophysiology with PKA activation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with electrophysiology distinguishing stimulus modalities, single lab, rigorous","pmids":["37146970"],"is_preprint":false},{"year":2022,"finding":"Piezo2 in lung microvascular endothelial cells is required for calcium influx and nitric oxide production in response to shear stress; Piezo2 knockdown impairs endothelial alignment, AKT phosphorylation, and NO production, and induces endothelial-to-mesenchymal transition markers.","method":"siRNA knockdown in MVECs, Ca2+ imaging, NO production assay, shear stress experiments, Western blotting","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA knockdown with multiple functional readouts, single lab","pmids":["36149769"],"is_preprint":false},{"year":2022,"finding":"Loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function in sensory neurons; linoleic acid supplementation increases PIEZO2 activity and mechano-excitability, and improves gait in Angelman syndrome mice.","method":"Ube3a-deficient mouse sensory neurons, human iPSC-derived sensory neurons with UBE3A knockdown, patch-clamp electrophysiology, actin filament staining, dietary intervention with behavioral readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems and orthogonal methods, but linoleic acid mechanism not fully resolved at molecular level","pmids":["36859399"],"is_preprint":false},{"year":2023,"finding":"FM 1-43 dye labeling of somatosensory neurons in vivo is dependent on PIEZO2 activity within peripheral nerve endings; FM 1-43 functions as a functional probe for mechanosensitivity via PIEZO2 activation in vivo.","method":"PIEZO2 conditional knockout mice, in vivo FM 1-43 labeling, nerve ending analysis","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO demonstrating PIEZO2-dependence of FM 1-43 labeling in vivo, single lab","pmids":["37321223"],"is_preprint":false},{"year":2023,"finding":"MrgprA3-expressing prurioceptors drive pruritogen-induced alloknesis through Piezo2; histamine and chloroquine sensitize Piezo2 channel function through PLC and PKCδ signaling; genetic ablation of Piezo2 from MrgprA3+ neurons dampens pruritogen-induced alloknesis.","method":"Conditional knockout mice (MrgprA3-specific Piezo2 ablation), pharmacological inhibitors (PLC, PKCδ), behavioral assays, patch-clamp electrophysiology","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with pharmacological pathway dissection, single lab","pmids":["36961815"],"is_preprint":false},{"year":2024,"finding":"Phosphatidic acid (PA) and lysophosphatidic acid (LPA) selectively inhibit PIEZO2 but not PIEZO1 when applied intracellularly; TMEM120A elevates cellular PA and LPA levels; optogenetic activation of phospholipase D (PLD), which generates PA, inhibits PIEZO2 but not PIEZO1; PLD inhibition increases PIEZO2 activity and mechanical sensitivity in mice.","method":"Patch-clamp electrophysiology, lipidomics, optogenetic PLD activation, pharmacological PLD inhibition, in vivo behavioral assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including optogenetics, lipidomics, pharmacology, and in vivo behavior, single lab","pmids":["39147733"],"is_preprint":false},{"year":2024,"finding":"PIEZO2 voltage-block regulates mechanical pain sensitivity: mutations at conserved arginine R2756 relieve voltage block and lower mechanical thresholds; in knock-in mice, nociceptor mechanosensitive currents are substantially sensitized while most mechanoreceptor currents are only mildly affected; this leads to behavioral hypersensitivity to noxious mechanical stimuli and ongoing nociceptor activity.","method":"Site-directed mutagenesis, knock-in mice (Piezo2R2756H and Piezo2R2756K), patch-clamp electrophysiology in isolated DRG neurons, single-unit extracellular electrophysiology, behavioral assays","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1 / Moderate — knock-in mice with biophysical mechanism validated by mutagenesis + electrophysiology + single-unit recordings + behavior, single lab but multiple rigorous methods","pmids":["38984717"],"is_preprint":false},{"year":2024,"finding":"TMC7 physically interacts with Piezo2 and β-actin in sensory neurons; TMC7 suppresses Piezo2 current amplitudes in co-expressing HEK293 cells; genetic deletion of TMC7 in DRG neurons increases the proportion of rapidly adapting currents and accelerates deactivation kinetics, enhancing mechanosensory sensitivity.","method":"Co-immunoprecipitation, patch-clamp electrophysiology in HEK293 cells and DRG neurons, conditional KO mice, behavioral assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP establishing physical interaction, heterologous functional assay, conditional KO with behavioral validation, single lab","pmids":["38568807"],"is_preprint":false},{"year":2024,"finding":"EndoA2 interacts with Piezo2 (co-immunoprecipitation, proximity ligation) and with KIF5B kinesin, promoting membrane trafficking of Piezo2 in DRG neurons; loss of EndoA2 in NF200+ DRG neurons damages Piezo2-mediated rapidly adapting MA currents, which are rescued by EndoA2 re-expression; KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and mechanical allodynia.","method":"Co-immunoprecipitation, proximity ligation assay, patch-clamp electrophysiology, conditional KO mice, behavioral assays in mice and non-human primates","journal":"Military Medical Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, proximity ligation, electrophysiology with rescue, KO behavioral phenotype, multiple orthogonal methods, single lab","pmids":["38475827"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 binds to m6A-modified PIEZO2 mRNA at a specific site (peak_26355) and induces PIEZO2 translation; Piezo2 expression in cardiac fibroblasts drives fibroblast activation and autophagy contributing to cardiac fibrosis; fibroblast-specific Piezo2 deficiency ameliorates cardiac fibrosis.","method":"RNA-seq, single-cell sequencing, m6A modification mapping, AAV-mediated fibroblast-specific shRNA knockdown, reconstitution experiments, histological and biochemical assays","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A site-specific modification with YTHDF1 binding demonstrated, cell-type-specific KD with fibrosis phenotype, single lab","pmids":["39498803"],"is_preprint":false},{"year":2025,"finding":"PIEZO2 is a major receptor in fat-innervating DRG neurons; PIEZO2 deletion in fat-innervating neurons induces transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation; a gain-of-function PIEZO2 mutant shifts adipose phenotypes in the opposite direction.","method":"Organ-targeted single-cell RNA sequencing, conditional neuron-specific KO, gain-of-function mutant mice, adipose tissue transcriptomics","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO and GOF mutant with transcriptional readout, single lab","pmids":["40054462"],"is_preprint":false},{"year":2024,"finding":"Vincristine potentiates PIEZO2 rapidly adapting MA currents in DRG neurons by enhancing static plasma membrane tension (SPMT); disruption of actin filaments with cytochalasin D reduces SPMT and abolishes vincristine-induced PIEZO2 potentiation and mechanical hypersensitivity.","method":"Patch-clamp electrophysiology in DRG neurons, actin disruption pharmacology, behavioral assays, PIEZO2 gene knockdown","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological rescue and gene knockdown, single lab","pmids":["37655331"],"is_preprint":false},{"year":2013,"finding":"GTP-dependent run-up of Piezo2-type rapidly adapting mechanically activated currents occurs in DRG neurons and in HEK293 cells heterologously expressing Piezo2; the run-up requires GTP (not GDP) in the intracellular solution and is absent in perforated patch configuration, indicating GTP-dependent intracellular regulation of Piezo2 channel function.","method":"Whole-cell patch-clamp electrophysiology in DRG neurons and HEK293 cells, perforated patch configuration, nucleotide substitution","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct electrophysiology with pharmacological dissection in native and heterologous systems, single lab","pmids":["24344923"],"is_preprint":false},{"year":2016,"finding":"Piezo2 expressed in the enterochromaffin (EC) cell model leads to mechanosensitive inward non-selective cation currents; both currents and serotonin release are inhibited by Piezo2 siRNA and antagonists (Gd3+ and D-GsMTx4); mucosal pressure increases serotonin release via submucosal 5-HT3 and 5-HT4 receptors.","method":"siRNA knockdown, patch-clamp electrophysiology, ELISA for serotonin, pharmacological inhibitors, Ussing chamber secretion assay","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with electrophysiology and serotonin release assay, single lab","pmids":["27392819"],"is_preprint":false},{"year":2020,"finding":"Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity: loss of Piezo2 in proprioceptive neurons (but not in chondrogenic or osteogenic lineages) leads to spine malalignment and hip dysplasia in mice, demonstrating a non-cell-autonomous role of proprioceptive PIEZO2 in joint morphogenesis.","method":"Lineage-specific conditional KO mice (proprioceptive, chondrogenic, osteogenic lineages), MRI/microCT skeletal analysis, genetic epistasis with Runx3 and Egr3 knockouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple lineage-specific conditional KOs with genetic epistasis analysis establishing non-cell-autonomous mechanism, single lab but rigorous","pmids":["32576830"],"is_preprint":false},{"year":2022,"finding":"Molecular dynamics simulations reveal that Piezo2 alters its local membrane composition, becoming enriched with specific lipids including phosphoinositides, and forms specific long-term interactions with various lipids at functionally relevant sites; this provides a structural basis for lipid-mediated regulation.","method":"Coarse-grained molecular dynamics simulations in complex mammalian membrane","journal":"The Journal of general physiology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation reported in abstract","pmids":["35861699"],"is_preprint":false}],"current_model":"PIEZO2 is a homotrimeric, propeller-shaped, mechanically activated non-selective cation channel that converts diverse physical stimuli (touch, proprioception, bladder stretch, urethral flow, ultrasound, shear stress) into electrical signals via rapidly adapting cation currents; its mechanogating involves force transmission through blade domains, a beam domain–CTD interface, specific pore-lining helix interactions, and cytoskeleton-coupled intrinsically disordered intracellular regions (including IDR5), while its activity is tuned by alternative splicing, voltage-dependent block at resting membrane potentials, PKA phosphorylation of multiple intracellular sites, lipid regulators (PI(3,5)P2 via Mtmr2; phosphatidic acid via PLD/TMEM120A), and interacting proteins (Nedd4-2, Pericentrin, TMC7, EndoA2/KIF5B), and by inflammatory signaling cascades (Epac1-cAMP, Gβγ-PI3K/MAPK, bradykinin-PKA/PKC, PLC-PKCδ) that sensitize the channel to underlie mechanical allodynia and hyperalgesia."},"narrative":{"mechanistic_narrative":"PIEZO2 is a rapidly adapting, mechanically activated non-selective cation channel that serves as the principal transducer converting physical force into electrical and calcium signals across diverse sensory and non-neuronal tissues [PMID:20813920, PMID:25471886]. It is the major channel for discriminative touch and proprioception, acting in Merkel cells, low-threshold mechanoreceptors, and muscle-spindle/Golgi-tendon proprioceptors [PMID:24717433, PMID:25471886, PMID:26551544], with human loss-of-function mutations causing selective loss of touch and proprioception and gain-of-function mutations causing Distal Arthrogryposis Type 5 by altering channel inactivation kinetics [PMID:23487782, PMID:27653382]. Beyond somatosensation, PIEZO2 mediates mechanotransduction in bladder urothelium and stretch-sensing neurons, enterochromaffin cells (driving serotonin release), and cochlear outer hair cells [PMID:30037999, PMID:33057202, PMID:34244441]. Its mechanogating depends on defined structural elements: blade domains transmit force and confer cold sensitivity, a beam–CTD interface and pore-lining helix interactions (Y2807) set mechanosensitivity, an intrinsically disordered cytosolic plug limits ion permeation, and the IDR5 linker couples the channel to cytoskeleton-transmitted forces, establishing that distinct stimuli (indentation versus stretch) engage distinct force-transmission pathways [PMID:31413193, PMID:31235572, PMID:35292651]. Channel output is tuned by extensive cell-type-specific alternative splicing, voltage-dependent block at resting potential, and inactivation kinetics that govern frequency filtering [PMID:29212024, PMID:28636944, PMID:38984717]. Activity is sensitized by inflammatory and GPCR signaling cascades—PKA/PKC, Epac1-cAMP, and Gβγ–PI3K/MAPK—underlying mechanical allodynia and itch [PMID:22921401, PMID:23575686, PMID:32227462, PMID:36961815], and is regulated by lipids (inhibition by phosphatidic acid via PLD/TMEM120A and by PI(3,5)P2 depletion via Mtmr2) and by interacting proteins controlling its current amplitude, trafficking, and membrane expression (Nedd4-2, TMC7, EndoA2/KIF5B, Pericentrin) [PMID:29521261, PMID:35819364, PMID:39147733, PMID:38568807, PMID:38475827]. PIEZO2-driven calcium influx also couples to downstream cytoskeletal and transcriptional programs, including a RhoA/YAP axis in cancer cell invasion [PMID:29432180].","teleology":[{"year":2010,"claim":"Established PIEZO2 as a bona fide component of mechanically activated channels, answering whether a discrete molecule underlies rapidly adapting touch currents.","evidence":"RNAi knockdown plus heterologous overexpression with patch-clamp in DRG neurons","pmids":["20813920"],"confidence":"High","gaps":["Did not establish whether PIEZO2 is the pore-forming subunit versus an accessory component","No structural or domain-level mechanism of gating"]},{"year":2013,"claim":"Linked PIEZO2 to human disease by showing gain-of-function mutations alter inactivation kinetics, connecting channel biophysics to Distal Arthrogryposis Type 5.","evidence":"Patch-clamp of mutant channels and whole-exome sequencing","pmids":["23487782"],"confidence":"High","gaps":["Did not resolve the structural basis of inactivation","Tissue-level mechanism connecting altered gating to joint contracture not defined"]},{"year":2013,"claim":"Defined inflammatory and intracellular signaling sensitization of PIEZO2, addressing how the channel becomes hyperactive in pain states.","evidence":"Pharmacological PKA/PKC and Epac manipulation, GTP substitution, electrophysiology, and in vivo knockdown with behavior","pmids":["22921401","23575686","24344923"],"confidence":"High","gaps":["Direct phosphorylation sites not yet mapped","Molecular identity of GTP-dependent regulator unknown"]},{"year":2014,"claim":"Identified PIEZO2 as the in vivo transducer for touch in Merkel cells and low-threshold mechanoreceptors, settling its physiological role in cutaneous sensation.","evidence":"Skin- and neuron-specific conditional knockout mice with DRG/skin-nerve electrophysiology, in vivo recordings, and behavior; CRISPR deletion in human stem-cell-derived neurons","pmids":["24717433","25471886","25469543"],"confidence":"High","gaps":["Residual non-PIEZO2 mechanotransduction in some afferents not explained","Cell-type specificity of channel properties not addressed"]},{"year":2015,"claim":"Established PIEZO2 as the principal proprioceptive channel, answering how body position is mechanically sensed.","evidence":"Two independent proprioceptor-specific knockout mouse lines with muscle-nerve recordings and behavior","pmids":["26551544","27184818"],"confidence":"High","gaps":["How force from muscle spindles reaches the channel not defined","Contribution of accessory structures to gating unknown"]},{"year":2016,"claim":"Confirmed PIEZO2 as a determinant of human mechanosensation, showing loss-of-function selectively impairs discriminative touch and proprioception.","evidence":"Whole-exome sequencing with functional assays, brain imaging, and psychophysical testing","pmids":["27653382"],"confidence":"High","gaps":["Did not address non-somatosensory roles later found in bladder, gut, and hearing"]},{"year":2016,"claim":"Identified native PIEZO2 regulators, revealing how lipids and accessory proteins tune mechanically activated currents.","evidence":"Mass-spectrometry native interactomics with Co-IP, domain-swap mutants, and electrophysiology (Mtmr2/PI(3,5)P2; Pericentrin)","pmids":["29521261","27345391"],"confidence":"High","gaps":["Pericentrin mechanism of modulation only partly resolved (Medium)","Whether lipid regulation operates in all PIEZO2-expressing tissues unknown"]},{"year":2017,"claim":"Showed that alternative splicing and inactivation kinetics diversify and filter PIEZO2 output, explaining tissue-specific channel behavior and frequency tuning.","evidence":"Isoform profiling and patch-clamp of splice variants and disease mutations with simulation","pmids":["29212024","28636944"],"confidence":"High","gaps":["Functional consequences of specific isoforms in vivo not established"]},{"year":2019,"claim":"Defined the structural elements of mechanogating, addressing how force is transmitted to channel opening and ion permeation.","evidence":"Structure-guided mutagenesis with single-channel and whole-cell electrophysiology; domain swapping for cold sensitivity; single-channel biophysical characterization","pmids":["31235572","31413193","31015490"],"confidence":"High","gaps":["High-resolution structure of gated states not provided in corpus","Curvature-sensitivity data from single cell type only (Medium)"]},{"year":2018,"claim":"Extended PIEZO2 function beyond somatosensation to gut and cancer, showing it drives enterochromaffin serotonin release and a RhoA/YAP invasion axis.","evidence":"Conditional KO, organoid Ca2+ imaging, serotonin ELISA; siRNA with RhoA activity assays and rescue in metastatic cells","pmids":["30037999","27392819","29432180"],"confidence":"High","gaps":["Mechanical stimulus source in vivo for EC cells not fully defined","Generality of the RhoA axis across cancers unknown"]},{"year":2020,"claim":"Identified PIEZO2 as the bladder and baroreceptor mechanosensor and dissected Gβγ-dependent potentiation, broadening its physiological footprint and sensitization logic.","evidence":"Cell-type-specific conditional KO with cystometry and human genetics; Co-IP and electrophysiology for Nedd4-2; pharmacological PI3K/MAPK dissection with behavior","pmids":["33057202","33352230","32227462","32576830"],"confidence":"High","gaps":["Nedd4-2 regulation shown by single-lab Co-IP/electrophysiology (Medium)","Non-cell-autonomous skeletal role mechanism downstream of proprioceptive firing not fully resolved"]},{"year":2021,"claim":"Demonstrated PIEZO2 roles in voiding and ultrasonic hearing, showing it cooperates with other channels in non-canonical sensory contexts.","evidence":"Urothelial conditional KO with ATP-release assays; outer-hair-cell KO with audiometry and cochlear Ca2+ imaging","pmids":["34464353","34244441"],"confidence":"High","gaps":["How PIEZO2 integrates with conventional hair-cell mechanotransduction unresolved"]},{"year":2022,"claim":"Resolved polymodal force transmission and lipid/protein tuning, showing distinct mechanical stimuli engage distinct domains and regulators.","evidence":"IDR5 deletion with poking/stretch electrophysiology; TMEM120A and phosphatidic acid lipid regulation; PKA multi-site mutagenesis; coarse-grained MD simulation of lipid enrichment","pmids":["35292651","35819364","37146970","39147733","35861699"],"confidence":"High","gaps":["Lipid enrichment from MD is computational only, no experimental validation (Low, #43)","How PA/TMEM120A regulation operates in vivo across tissues incomplete"]},{"year":2024,"claim":"Defined voltage block as a tunable pain gate and identified trafficking and expression regulators, connecting channel availability and biophysics to mechanical pain.","evidence":"R2756 knock-in mice with electrophysiology and behavior; TMC7 and EndoA2/KIF5B Co-IP, conditional KO and rescue; vincristine/actin-tension pharmacology; YTHDF1 m6A regulation of PIEZO2 translation in cardiac fibroblasts","pmids":["38984717","38568807","38475827","37655331","39498803"],"confidence":"High","gaps":["m6A/YTHDF1 control of PIEZO2 shown in single tissue context (Medium)","EndoA2/TMC7 effects validated largely in one lab each"]},{"year":2025,"claim":"Extended PIEZO2 to metabolic organ crosstalk, showing fat-innervating PIEZO2 neurons shape adipose transcriptional programs.","evidence":"Neuron-specific conditional KO and gain-of-function mutant mice with adipose single-cell transcriptomics","pmids":["40054462"],"confidence":"Medium","gaps":["Mechanical stimulus sensed in fat not identified","Causal signaling from PIEZO2 activation to adipose program not resolved"]},{"year":null,"claim":"How distinct force-transmission pathways (membrane tension versus cytoskeleton via IDR5), lipid microenvironment, and the full set of accessory proteins integrate to produce tissue-specific gating thresholds remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified high-resolution structure of gated/lipid-bound states in corpus","In vivo relevance of many regulators tested only heterologously","Mechanism converting channel activity to downstream transcriptional/secretory programs incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,5,20]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,4,5,18,20]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,20,36]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[4,5,8,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,22,32]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,8,10]}],"complexes":[],"partners":["MTMR2","NEDD4-2","TMC7","ENDOA2","KIF5B","PERICENTRIN","TMEM120A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H5I5","full_name":"Piezo-type mechanosensitive ion channel component 2","aliases":["Protein FAM38B"],"length_aa":2752,"mass_kda":318.1,"function":"Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain (PubMed:37590348). Piezo channels are homotrimeric three-blade propeller-shaped structures that utilize a cap-motion and plug-and-latch mechanism to gate their ion-conducting pathways (PubMed:37590348). Expressed in sensory neurons, is essential for diverse physiological processes, including respiratory control, systemic metabolism, urinary function, and proprioception (By similarity). Mediates airway stretch sensing, enabling efficient respiration at birth and maintaining normal breathing in adults (By similarity). It regulates brown and beige adipose tissue morphology and function, preventing systemic hypermetabolism (By similarity). In the lower urinary tract, acts as a sensor in both the bladder urothelium and innervating sensory neurons being required for bladder-stretch sensing and urethral micturition reflexes, ensuring proper urinary function (PubMed:33057202). Additionally, PIEZO2 serves as the principal mechanotransducer in proprioceptors, facilitating proprioception and coordinated body movements (By similarity). In inner ear hair cells, PIEZO1/2 subunits may constitute part of the mechanotransducer (MET) non-selective cation channel complex where they may act as pore-forming ion-conducting component in the complex (By similarity). Required for Merkel-cell mechanotransduction (By similarity). Plays a major role in light-touch mechanosensation (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H5I5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIEZO2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":77,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIEZO2","total_profiled":1310},"omim":[{"mim_id":"621342","title":"TRANSMEMBRANE PROTEIN 87A; TMEM87A","url":"https://www.omim.org/entry/621342"},{"mim_id":"617146","title":"ARTHROGRYPOSIS, DISTAL, WITH IMPAIRED PROPRIOCEPTION AND TOUCH; DAIPT","url":"https://www.omim.org/entry/617146"},{"mim_id":"613629","title":"PIEZO-TYPE MECHANOSENSITIVE ION CHANNEL COMPONENT 2; PIEZO2","url":"https://www.omim.org/entry/613629"},{"mim_id":"611184","title":"PIEZO-TYPE MECHANOSENSITIVE ION CHANNEL COMPONENT 1; PIEZO1","url":"https://www.omim.org/entry/611184"},{"mim_id":"248700","title":"MARDEN-WALKER SYNDROME; MWKS","url":"https://www.omim.org/entry/248700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIEZO2"},"hgnc":{"alias_symbol":["FLJ23403","FLJ23144","HsT748","HsT771","FLJ34907"],"prev_symbol":["FAM38B2","C18orf30","C18orf58","FAM38B"]},"alphafold":{"accession":"Q9H5I5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5I5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5I5-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5I5-3-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIEZO2","jax_strain_url":"https://www.jax.org/strain/search?query=PIEZO2"},"sequence":{"accession":"Q9H5I5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H5I5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H5I5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5I5"}},"corpus_meta":[{"pmid":"20813920","id":"PMC_20813920","title":"Piezo1 and Piezo2 are essential components of 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Overexpression of mouse Piezo2 in cells induced rapidly adapting mechanically activated currents; knockdown of Piezo2 in dorsal root ganglion neurons specifically reduced rapidly adapting MA currents.\",\n      \"method\": \"RNA interference knockdown, heterologous overexpression, electrophysiology (patch-clamp)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RNAi knockdown + overexpression + electrophysiology), replicated across cell types, foundational study\",\n      \"pmids\": [\"20813920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Piezo2-mediated mechanically activated currents in sensory neurons are enhanced by bradykinin receptor beta 2 (BDKRB2) activation via PKA and PKC signaling; PKA and PKC agonists directly enhance piezo2 activity, and BDKRB2-mediated effects are abolished by PKA and PKC inhibitors.\",\n      \"method\": \"Heterologous expression, pharmacological activation/inhibition, patch-clamp electrophysiology in sensory neurons and HEK cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal pharmacological interventions plus electrophysiology in both native neurons and heterologous system, single lab\",\n      \"pmids\": [\"22921401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PIEZO2 gain-of-function mutations (E2727del and I802F) affect channel inactivation kinetics: E2727del slows inactivation and both mutations cause faster recovery from inactivation, resulting in increased channel activity in response to mechanical stimuli, linking PIEZO2 dysfunction to Distal Arthrogryposis Type 5.\",\n      \"method\": \"Electrophysiological characterization of mutant PIEZO2 expressed in cells (patch-clamp), whole-exome sequencing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological characterization of two independent disease mutations with defined biophysical mechanism, single lab\",\n      \"pmids\": [\"23487782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Epac1 activation potentiates Piezo2-mediated mechanotransduction: the Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents via Piezo2 in a manner dependent on cytosolic calcium and cytoskeleton integrity, but independent of PKC or PKA; in vivo Piezo2 knockdown attenuates 8-pCPT-induced mechanical allodynia.\",\n      \"method\": \"Patch-clamp electrophysiology, pharmacological manipulation, in vivo knockdown, behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, pharmacology, in vivo knockdown, behavior), single lab\",\n      \"pmids\": [\"23575686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Piezo2 is the Merkel-cell mechanotransduction channel: Merkel cells produce touch-sensitive currents in vitro that completely depend on Piezo2, as shown by skin-specific Piezo2 conditional knockout mice lacking Merkel-cell mechanosensitivity; loss also reduces slowly adapting in vivo firing rates and decreases behavioral responses to gentle touch.\",\n      \"method\": \"Conditional knockout mice (skin-specific), patch-clamp electrophysiology, in vivo nerve recordings, behavioral assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal phenotypic readouts (electrophysiology, in vivo recordings, behavior), replicated concept across labs\",\n      \"pmids\": [\"24717433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Piezo2 is the major transducer for touch sensation: mice lacking Piezo2 in adult sensory neurons and Merkel cells exhibit profound loss of touch sensation; most rapidly adapting MA currents in DRG cultures are absent; mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2 in ex vivo skin-nerve preparations.\",\n      \"method\": \"Conditional knockout mice, patch-clamp electrophysiology in DRG cultures, ex vivo skin-nerve preparation electrophysiology, behavioral assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple independent assays (DRG electrophysiology, ex vivo nerve prep, behavior), replicated concept\",\n      \"pmids\": [\"25471886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors: CRISPR/Cas9-mediated PIEZO2 gene deletion abolishes mechanosensitivity in hES cell-derived sensory neurons.\",\n      \"method\": \"CRISPR/Cas9 gene deletion, hES/hiPS cell differentiation protocol, patch-clamp electrophysiology\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic knockout with direct functional readout in human-derived neurons, single lab with rigorous controls\",\n      \"pmids\": [\"25469543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Combined directed expression of Piezo1 and Piezo2 in chondrocytes produces potentiated mechanically induced Ca2+ signals and electrical currents compared with single-Piezo expression; Piezo1- or Piezo2-specific siRNA inhibits mechanically evoked Ca2+ transients in primary articular chondrocytes.\",\n      \"method\": \"Heterologous co-expression, siRNA knockdown, atomic force microscopy-induced Ca2+ imaging, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-expression and siRNA knockdown with Ca2+ imaging and electrophysiology, single lab\",\n      \"pmids\": [\"25385580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Piezo2 is the principal mechanotransduction channel for proprioception: Piezo2 is expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs; two independent mouse lines lacking Piezo2 in proprioceptive neurons show severely uncoordinated movements, and stretch-induced firing of proprioceptors in muscle-nerve recordings is markedly reduced.\",\n      \"method\": \"Conditional knockout mice (two independent lines), immunohistochemistry, in vitro patch-clamp, muscle-nerve electrophysiology, behavioral analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO lines with multiple orthogonal assays (patch-clamp, muscle-nerve recordings, behavior)\",\n      \"pmids\": [\"26551544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function compound mutations in PIEZO2 in humans cause selective loss of discriminative touch perception and profoundly decreased proprioception, confirming PIEZO2 as a determinant of mechanosensation in humans; functional brain imaging and psychophysical testing established the selective sensory deficits.\",\n      \"method\": \"Whole-exome sequencing, in vitro functional assays, messenger RNA assays, functional brain imaging, psychophysical and kinematic testing\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic study with multiple orthogonal functional validation methods, single-center but rigorous\",\n      \"pmids\": [\"27653382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Piezo2 in mesencephalic trigeminal nucleus proprioceptive neurons produces rapidly adapting mechanically activated currents that are fully dependent on Piezo2; selective deletion of Piezo2 in proprioceptors causes deficits in balance and coordination.\",\n      \"method\": \"Conditional knockout mice (proprioceptor-specific), patch-clamp electrophysiology, behavioral assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with electrophysiology and behavioral readout, single lab\",\n      \"pmids\": [\"27184818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mtmr2 (myotubularin related protein-2), a PI phosphatase, was identified as a native Piezo2 interactor in DRG; Mtmr2 attenuates Piezo2-mediated rapidly adapting MA currents through depletion of PI(3,5)P2; a PI(3,5)P2 binding region specific to Piezo2 (not Piezo1) confers sensitivity to Mtmr2 regulation.\",\n      \"method\": \"Mass spectrometry-based native interactomics, co-immunoprecipitation, patch-clamp electrophysiology, pharmacological inhibitors, domain-swapped Piezo2 mutant analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — native interactomics, functional electrophysiology, domain-swap mutagenesis, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"29521261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pericentrin, identified in a native Piezo2 interactomics screen of mouse DRG, modulates Piezo2 activity and membrane expression in somatosensory neurons.\",\n      \"method\": \"Mass spectrometry-based native interactomics, functional electrophysiology, membrane expression assay\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS interactomics followed by functional validation, single lab\",\n      \"pmids\": [\"27345391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Piezo2 is extensively alternatively spliced, producing isoforms with distinct biophysical properties including differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics; splicing is cell-type specific even within sensory ganglia.\",\n      \"method\": \"RNA sequencing/isoform profiling, biophysical characterization of splice variants by patch-clamp electrophysiology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiological characterization of multiple splice variants with multiple biophysical parameters, single lab, rigorous\",\n      \"pmids\": [\"29212024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Channel inactivation is the molecular mechanism underlying frequency filtering of Piezo2 (and Piezo1) in response to repetitive mechanical stimuli; human disease-related point mutations that alter inactivation kinetics correspondingly alter frequency filtering.\",\n      \"method\": \"Patch-clamp electrophysiology of heterologously expressed channels, numerical simulations, disease-related point mutations\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology with mutagenesis and simulation, single lab, rigorous mechanistic analysis\",\n      \"pmids\": [\"28636944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"D-GsMTx4 (spider peptide) reversibly and dose-dependently inhibits Piezo2 mechanosensitive currents in response to mechanical force, acting on both potency and efficacy.\",\n      \"method\": \"Patch-clamp electrophysiology in HEK293 cells overexpressing human Piezo2, dose-response pharmacology\",\n      \"journal\": \"Channels (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct electrophysiology in heterologous system, single lab, single method\",\n      \"pmids\": [\"28085630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Piezo2 channel-mediated Ca2+ influx activates RhoA in brain metastatic cancer cells, controlling formation and orientation of stress fibers and focal adhesions; mechanism involves Fyn kinase recruitment to the cell leading edge and calpain activation; YAP nuclear translocation and cancer invasion phenotypes depend on this Piezo2-RhoA axis.\",\n      \"method\": \"siRNA knockdown, Ca2+ imaging, RhoA activity assays, confocal microscopy, dominant-positive RhoA rescue experiments, invasion/migration assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus rescue with dominant-positive RhoA/mDia1, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"29432180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Piezo2 is the primary mechanotransducer in enterochromaffin cells: mechanical stimulation leads to Piezo2-dependent inward ionic currents, intracellular Ca2+ increase, and serotonin release; conditional knockout of intestinal epithelial Piezo2 significantly decreases mechanically stimulated epithelial secretion.\",\n      \"method\": \"Lineage tracing, super-resolution microscopy, patch-clamp electrophysiology, Ca2+ imaging in organoids, ELISA for serotonin, conditional knockout mice, siRNA knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, serotonin ELISA, conditional KO, siRNA) in multiple model systems\",\n      \"pmids\": [\"30037999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cold potentiates Piezo2-dependent mechanically activated currents in vertebrate mechanoreceptors; cold sensitivity of Piezo2 is dependent on its blade domains, which render the channel resistant to cold-induced perturbations of the plasma membrane physical properties; this is a distinct mechanism from Piezo1 cold sensitivity.\",\n      \"method\": \"Patch-clamp electrophysiology in mechanoreceptors and heterologous systems with Piezo2 orthologs, domain mutagenesis/swapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology with domain mutagenesis across species, single lab, rigorous\",\n      \"pmids\": [\"31413193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Charged amino acids at the beam domain–CTD interface and hydrophobic interactions between Y2807 of the CTD and pore-lining helices are required for normal mechanosensitivity of PIEZO2; an intrinsically disordered domain adjacent to the beam acts as a cytosolic plug limiting ion permeation by clogging the inner vestibule.\",\n      \"method\": \"Site-directed mutagenesis, patch-clamp electrophysiology (single-channel and whole-cell recordings), structure-guided analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-guided mutagenesis with single-channel and whole-cell electrophysiology, mechanistic domain interface identified, single lab\",\n      \"pmids\": [\"31235572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Piezo2 is a low-threshold, positive pressure-specific, curvature-sensitive, mechanically activated cation channel; single channel conductance is ~28.6 pS in Merkel cell carcinoma cells; positive pressure ≥5 mmHg activates Piezo2 while negative pressure does not (unlike Piezo1).\",\n      \"method\": \"Patch-clamp electrophysiology (cell-attached and whole-cell), step indentation and pressure application protocols\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct single-channel electrophysiology but single lab, single cell type\",\n      \"pmids\": [\"31015490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIEZO2 acts as a mechanosensor in both bladder urothelium and innervating sensory neurons; humans and mice lacking functional PIEZO2 have impaired bladder control and deficient bladder-filling sensation; PIEZO2 is required for low-threshold bladder-stretch sensing and urethral micturition reflexes.\",\n      \"method\": \"Conditional knockout mice (urothelial and neuron-specific), cystometry, behavioral bladder assessment, human genetic analysis with patient-reported outcomes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in two cell types plus human genetic validation with multiple functional readouts\",\n      \"pmids\": [\"33057202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gi-coupled receptor activation potentiates Piezo2 currents via Gβγ in a manner dependent on downstream PI3K and MAPK kinases; sumatriptan (Gi-coupled 5-HT1B/1D receptor agonist) increases mechanical sensitivity in mice, abolished by PI3K and MAPK inhibition; Piezo1 currents are inhibited (not potentiated) by the same pathway.\",\n      \"method\": \"Patch-clamp electrophysiology in DRG neurons and heterologous Piezo2 expression, pharmacological inhibitors, in vivo behavioral assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiology in native neurons and heterologous system, pharmacological dissection of pathway, in vivo behavioral validation, single lab\",\n      \"pmids\": [\"32227462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nedd4-2 interacts with Piezo2 (co-immunoprecipitation) and inhibits Piezo2 MA currents in co-expressed HEK293T cells; Nedd4-2 upregulation in baroreceptor nodose ganglia neurons of hypertensive rats leads to downregulation of Piezo2, reducing RA-MA currents and impairing baroreflex.\",\n      \"method\": \"Co-immunoprecipitation, patch-clamp electrophysiology in HEK293T cells, siRNA knockdown in vivo, blood pressure measurement, spontaneously hypertensive rat model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP plus functional electrophysiology, in vivo KD with blood pressure phenotype, single lab\",\n      \"pmids\": [\"33352230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Urothelial PIEZO2 (expressed in a subset of umbrella cells) is required for normal voiding function; male Piezo2-KO mice exhibit urinary incontinence; dual Piezo1/2-KO mice show decreased urothelial mechanical responses, diminished ATP release, and bladder hypoactivity.\",\n      \"method\": \"Conditional urothelial KO mice (Piezo2, Piezo1, dual), voiding behavior monitoring, urothelial mechanosensitivity assays, ATP release measurement\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with multiple functional readouts (ATP release, bladder activity, behavior), replicates and extends PMID 33057202\",\n      \"pmids\": [\"34464353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIEZO2 mediates ultrasonic hearing via cochlear outer hair cells: knockout of PIEZO2 in outer hair cells (OHCs) specifically abolishes associative learning during ultrasonic frequency exposure; ultrasonic Ca2+ transduction in cochlea requires both PIEZO2 and the conventional hair-cell mechanotransduction channel.\",\n      \"method\": \"Cell-type-specific knockout mice, audiometry, acoustically associative freezing behavior, ex vivo cochlear Ca2+ imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with multiple orthogonal readouts (audiometry, behavior, Ca2+ imaging), single lab\",\n      \"pmids\": [\"34244441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The intrinsically disordered linker IDR5 (between transmembrane helices 12 and 13) is required for activation of PIEZO2 by cytoskeleton-transmitted forces; IDR5 deletion abolishes PIEZO2-mediated inhibition of neurite outgrowth and partially reduces cell indentation sensitivity but does not alter stretch sensitivity, indicating PIEZO2 detects different mechanical stimuli via different force transmission pathways.\",\n      \"method\": \"Site-directed mutagenesis/deletion, patch-clamp electrophysiology (poking and stretch), neurite outgrowth assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with multiple functional assays distinguishing force transmission pathways, single lab\",\n      \"pmids\": [\"35292651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM120A coexpression decreases the amplitudes of mechanically activated PIEZO2 currents and increases their activation threshold; TMEM120A does not inhibit PIEZO1 or TREK1; siRNA knockdown of Tmem120a in DRG neurons increases rapidly adapting MA current amplitudes and decreases thresholds.\",\n      \"method\": \"Heterologous co-expression, patch-clamp electrophysiology, siRNA knockdown in DRG neurons\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct electrophysiology in heterologous and native neuron systems with both overexpression and knockdown, single lab\",\n      \"pmids\": [\"35819364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PKA-dependent modulation of PIEZO2 requires a combination of nine putative PKA phosphorylation sites on four different intracellular disordered regions; mutation of all nine sites abolishes PKA-induced sensitization; PKA modulates PIEZO2 responses to cell indentation but not to pressure-induced membrane stretch, suggesting polymodal mechanosensing through different domains.\",\n      \"method\": \"Phosphorylation site prediction, site-directed mutagenesis, patch-clamp electrophysiology with PKA activation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with electrophysiology distinguishing stimulus modalities, single lab, rigorous\",\n      \"pmids\": [\"37146970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo2 in lung microvascular endothelial cells is required for calcium influx and nitric oxide production in response to shear stress; Piezo2 knockdown impairs endothelial alignment, AKT phosphorylation, and NO production, and induces endothelial-to-mesenchymal transition markers.\",\n      \"method\": \"siRNA knockdown in MVECs, Ca2+ imaging, NO production assay, shear stress experiments, Western blotting\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA knockdown with multiple functional readouts, single lab\",\n      \"pmids\": [\"36149769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function in sensory neurons; linoleic acid supplementation increases PIEZO2 activity and mechano-excitability, and improves gait in Angelman syndrome mice.\",\n      \"method\": \"Ube3a-deficient mouse sensory neurons, human iPSC-derived sensory neurons with UBE3A knockdown, patch-clamp electrophysiology, actin filament staining, dietary intervention with behavioral readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems and orthogonal methods, but linoleic acid mechanism not fully resolved at molecular level\",\n      \"pmids\": [\"36859399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FM 1-43 dye labeling of somatosensory neurons in vivo is dependent on PIEZO2 activity within peripheral nerve endings; FM 1-43 functions as a functional probe for mechanosensitivity via PIEZO2 activation in vivo.\",\n      \"method\": \"PIEZO2 conditional knockout mice, in vivo FM 1-43 labeling, nerve ending analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO demonstrating PIEZO2-dependence of FM 1-43 labeling in vivo, single lab\",\n      \"pmids\": [\"37321223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MrgprA3-expressing prurioceptors drive pruritogen-induced alloknesis through Piezo2; histamine and chloroquine sensitize Piezo2 channel function through PLC and PKCδ signaling; genetic ablation of Piezo2 from MrgprA3+ neurons dampens pruritogen-induced alloknesis.\",\n      \"method\": \"Conditional knockout mice (MrgprA3-specific Piezo2 ablation), pharmacological inhibitors (PLC, PKCδ), behavioral assays, patch-clamp electrophysiology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"36961815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Phosphatidic acid (PA) and lysophosphatidic acid (LPA) selectively inhibit PIEZO2 but not PIEZO1 when applied intracellularly; TMEM120A elevates cellular PA and LPA levels; optogenetic activation of phospholipase D (PLD), which generates PA, inhibits PIEZO2 but not PIEZO1; PLD inhibition increases PIEZO2 activity and mechanical sensitivity in mice.\",\n      \"method\": \"Patch-clamp electrophysiology, lipidomics, optogenetic PLD activation, pharmacological PLD inhibition, in vivo behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including optogenetics, lipidomics, pharmacology, and in vivo behavior, single lab\",\n      \"pmids\": [\"39147733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIEZO2 voltage-block regulates mechanical pain sensitivity: mutations at conserved arginine R2756 relieve voltage block and lower mechanical thresholds; in knock-in mice, nociceptor mechanosensitive currents are substantially sensitized while most mechanoreceptor currents are only mildly affected; this leads to behavioral hypersensitivity to noxious mechanical stimuli and ongoing nociceptor activity.\",\n      \"method\": \"Site-directed mutagenesis, knock-in mice (Piezo2R2756H and Piezo2R2756K), patch-clamp electrophysiology in isolated DRG neurons, single-unit extracellular electrophysiology, behavioral assays\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — knock-in mice with biophysical mechanism validated by mutagenesis + electrophysiology + single-unit recordings + behavior, single lab but multiple rigorous methods\",\n      \"pmids\": [\"38984717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMC7 physically interacts with Piezo2 and β-actin in sensory neurons; TMC7 suppresses Piezo2 current amplitudes in co-expressing HEK293 cells; genetic deletion of TMC7 in DRG neurons increases the proportion of rapidly adapting currents and accelerates deactivation kinetics, enhancing mechanosensory sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, patch-clamp electrophysiology in HEK293 cells and DRG neurons, conditional KO mice, behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP establishing physical interaction, heterologous functional assay, conditional KO with behavioral validation, single lab\",\n      \"pmids\": [\"38568807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EndoA2 interacts with Piezo2 (co-immunoprecipitation, proximity ligation) and with KIF5B kinesin, promoting membrane trafficking of Piezo2 in DRG neurons; loss of EndoA2 in NF200+ DRG neurons damages Piezo2-mediated rapidly adapting MA currents, which are rescued by EndoA2 re-expression; KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and mechanical allodynia.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, patch-clamp electrophysiology, conditional KO mice, behavioral assays in mice and non-human primates\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, proximity ligation, electrophysiology with rescue, KO behavioral phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38475827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 binds to m6A-modified PIEZO2 mRNA at a specific site (peak_26355) and induces PIEZO2 translation; Piezo2 expression in cardiac fibroblasts drives fibroblast activation and autophagy contributing to cardiac fibrosis; fibroblast-specific Piezo2 deficiency ameliorates cardiac fibrosis.\",\n      \"method\": \"RNA-seq, single-cell sequencing, m6A modification mapping, AAV-mediated fibroblast-specific shRNA knockdown, reconstitution experiments, histological and biochemical assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A site-specific modification with YTHDF1 binding demonstrated, cell-type-specific KD with fibrosis phenotype, single lab\",\n      \"pmids\": [\"39498803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIEZO2 is a major receptor in fat-innervating DRG neurons; PIEZO2 deletion in fat-innervating neurons induces transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation; a gain-of-function PIEZO2 mutant shifts adipose phenotypes in the opposite direction.\",\n      \"method\": \"Organ-targeted single-cell RNA sequencing, conditional neuron-specific KO, gain-of-function mutant mice, adipose tissue transcriptomics\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO and GOF mutant with transcriptional readout, single lab\",\n      \"pmids\": [\"40054462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Vincristine potentiates PIEZO2 rapidly adapting MA currents in DRG neurons by enhancing static plasma membrane tension (SPMT); disruption of actin filaments with cytochalasin D reduces SPMT and abolishes vincristine-induced PIEZO2 potentiation and mechanical hypersensitivity.\",\n      \"method\": \"Patch-clamp electrophysiology in DRG neurons, actin disruption pharmacology, behavioral assays, PIEZO2 gene knockdown\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological rescue and gene knockdown, single lab\",\n      \"pmids\": [\"37655331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GTP-dependent run-up of Piezo2-type rapidly adapting mechanically activated currents occurs in DRG neurons and in HEK293 cells heterologously expressing Piezo2; the run-up requires GTP (not GDP) in the intracellular solution and is absent in perforated patch configuration, indicating GTP-dependent intracellular regulation of Piezo2 channel function.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in DRG neurons and HEK293 cells, perforated patch configuration, nucleotide substitution\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct electrophysiology with pharmacological dissection in native and heterologous systems, single lab\",\n      \"pmids\": [\"24344923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Piezo2 expressed in the enterochromaffin (EC) cell model leads to mechanosensitive inward non-selective cation currents; both currents and serotonin release are inhibited by Piezo2 siRNA and antagonists (Gd3+ and D-GsMTx4); mucosal pressure increases serotonin release via submucosal 5-HT3 and 5-HT4 receptors.\",\n      \"method\": \"siRNA knockdown, patch-clamp electrophysiology, ELISA for serotonin, pharmacological inhibitors, Ussing chamber secretion assay\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with electrophysiology and serotonin release assay, single lab\",\n      \"pmids\": [\"27392819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity: loss of Piezo2 in proprioceptive neurons (but not in chondrogenic or osteogenic lineages) leads to spine malalignment and hip dysplasia in mice, demonstrating a non-cell-autonomous role of proprioceptive PIEZO2 in joint morphogenesis.\",\n      \"method\": \"Lineage-specific conditional KO mice (proprioceptive, chondrogenic, osteogenic lineages), MRI/microCT skeletal analysis, genetic epistasis with Runx3 and Egr3 knockouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple lineage-specific conditional KOs with genetic epistasis analysis establishing non-cell-autonomous mechanism, single lab but rigorous\",\n      \"pmids\": [\"32576830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Molecular dynamics simulations reveal that Piezo2 alters its local membrane composition, becoming enriched with specific lipids including phosphoinositides, and forms specific long-term interactions with various lipids at functionally relevant sites; this provides a structural basis for lipid-mediated regulation.\",\n      \"method\": \"Coarse-grained molecular dynamics simulations in complex mammalian membrane\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation reported in abstract\",\n      \"pmids\": [\"35861699\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIEZO2 is a homotrimeric, propeller-shaped, mechanically activated non-selective cation channel that converts diverse physical stimuli (touch, proprioception, bladder stretch, urethral flow, ultrasound, shear stress) into electrical signals via rapidly adapting cation currents; its mechanogating involves force transmission through blade domains, a beam domain–CTD interface, specific pore-lining helix interactions, and cytoskeleton-coupled intrinsically disordered intracellular regions (including IDR5), while its activity is tuned by alternative splicing, voltage-dependent block at resting membrane potentials, PKA phosphorylation of multiple intracellular sites, lipid regulators (PI(3,5)P2 via Mtmr2; phosphatidic acid via PLD/TMEM120A), and interacting proteins (Nedd4-2, Pericentrin, TMC7, EndoA2/KIF5B), and by inflammatory signaling cascades (Epac1-cAMP, Gβγ-PI3K/MAPK, bradykinin-PKA/PKC, PLC-PKCδ) that sensitize the channel to underlie mechanical allodynia and hyperalgesia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIEZO2 is a rapidly adapting, mechanically activated non-selective cation channel that serves as the principal transducer converting physical force into electrical and calcium signals across diverse sensory and non-neuronal tissues [#0, #5]. It is the major channel for discriminative touch and proprioception, acting in Merkel cells, low-threshold mechanoreceptors, and muscle-spindle/Golgi-tendon proprioceptors [#4, #5, #8], with human loss-of-function mutations causing selective loss of touch and proprioception and gain-of-function mutations causing Distal Arthrogryposis Type 5 by altering channel inactivation kinetics [#2, #9]. Beyond somatosensation, PIEZO2 mediates mechanotransduction in bladder urothelium and stretch-sensing neurons, enterochromaffin cells (driving serotonin release), and cochlear outer hair cells [#17, #21, #25]. Its mechanogating depends on defined structural elements: blade domains transmit force and confer cold sensitivity, a beam–CTD interface and pore-lining helix interactions (Y2807) set mechanosensitivity, an intrinsically disordered cytosolic plug limits ion permeation, and the IDR5 linker couples the channel to cytoskeleton-transmitted forces, establishing that distinct stimuli (indentation versus stretch) engage distinct force-transmission pathways [#18, #19, #26]. Channel output is tuned by extensive cell-type-specific alternative splicing, voltage-dependent block at resting potential, and inactivation kinetics that govern frequency filtering [#13, #14, #34]. Activity is sensitized by inflammatory and GPCR signaling cascades—PKA/PKC, Epac1-cAMP, and Gβγ–PI3K/MAPK—underlying mechanical allodynia and itch [#1, #3, #22, #32], and is regulated by lipids (inhibition by phosphatidic acid via PLD/TMEM120A and by PI(3,5)P2 depletion via Mtmr2) and by interacting proteins controlling its current amplitude, trafficking, and membrane expression (Nedd4-2, TMC7, EndoA2/KIF5B, Pericentrin) [#11, #27, #33, #35, #36]. PIEZO2-driven calcium influx also couples to downstream cytoskeletal and transcriptional programs, including a RhoA/YAP axis in cancer cell invasion [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established PIEZO2 as a bona fide component of mechanically activated channels, answering whether a discrete molecule underlies rapidly adapting touch currents.\",\n      \"evidence\": \"RNAi knockdown plus heterologous overexpression with patch-clamp in DRG neurons\",\n      \"pmids\": [\"20813920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether PIEZO2 is the pore-forming subunit versus an accessory component\", \"No structural or domain-level mechanism of gating\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked PIEZO2 to human disease by showing gain-of-function mutations alter inactivation kinetics, connecting channel biophysics to Distal Arthrogryposis Type 5.\",\n      \"evidence\": \"Patch-clamp of mutant channels and whole-exome sequencing\",\n      \"pmids\": [\"23487782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of inactivation\", \"Tissue-level mechanism connecting altered gating to joint contracture not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined inflammatory and intracellular signaling sensitization of PIEZO2, addressing how the channel becomes hyperactive in pain states.\",\n      \"evidence\": \"Pharmacological PKA/PKC and Epac manipulation, GTP substitution, electrophysiology, and in vivo knockdown with behavior\",\n      \"pmids\": [\"22921401\", \"23575686\", \"24344923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation sites not yet mapped\", \"Molecular identity of GTP-dependent regulator unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified PIEZO2 as the in vivo transducer for touch in Merkel cells and low-threshold mechanoreceptors, settling its physiological role in cutaneous sensation.\",\n      \"evidence\": \"Skin- and neuron-specific conditional knockout mice with DRG/skin-nerve electrophysiology, in vivo recordings, and behavior; CRISPR deletion in human stem-cell-derived neurons\",\n      \"pmids\": [\"24717433\", \"25471886\", \"25469543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual non-PIEZO2 mechanotransduction in some afferents not explained\", \"Cell-type specificity of channel properties not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established PIEZO2 as the principal proprioceptive channel, answering how body position is mechanically sensed.\",\n      \"evidence\": \"Two independent proprioceptor-specific knockout mouse lines with muscle-nerve recordings and behavior\",\n      \"pmids\": [\"26551544\", \"27184818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How force from muscle spindles reaches the channel not defined\", \"Contribution of accessory structures to gating unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed PIEZO2 as a determinant of human mechanosensation, showing loss-of-function selectively impairs discriminative touch and proprioception.\",\n      \"evidence\": \"Whole-exome sequencing with functional assays, brain imaging, and psychophysical testing\",\n      \"pmids\": [\"27653382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address non-somatosensory roles later found in bladder, gut, and hearing\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified native PIEZO2 regulators, revealing how lipids and accessory proteins tune mechanically activated currents.\",\n      \"evidence\": \"Mass-spectrometry native interactomics with Co-IP, domain-swap mutants, and electrophysiology (Mtmr2/PI(3,5)P2; Pericentrin)\",\n      \"pmids\": [\"29521261\", \"27345391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pericentrin mechanism of modulation only partly resolved (Medium)\", \"Whether lipid regulation operates in all PIEZO2-expressing tissues unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that alternative splicing and inactivation kinetics diversify and filter PIEZO2 output, explaining tissue-specific channel behavior and frequency tuning.\",\n      \"evidence\": \"Isoform profiling and patch-clamp of splice variants and disease mutations with simulation\",\n      \"pmids\": [\"29212024\", \"28636944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of specific isoforms in vivo not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the structural elements of mechanogating, addressing how force is transmitted to channel opening and ion permeation.\",\n      \"evidence\": \"Structure-guided mutagenesis with single-channel and whole-cell electrophysiology; domain swapping for cold sensitivity; single-channel biophysical characterization\",\n      \"pmids\": [\"31235572\", \"31413193\", \"31015490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of gated states not provided in corpus\", \"Curvature-sensitivity data from single cell type only (Medium)\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended PIEZO2 function beyond somatosensation to gut and cancer, showing it drives enterochromaffin serotonin release and a RhoA/YAP invasion axis.\",\n      \"evidence\": \"Conditional KO, organoid Ca2+ imaging, serotonin ELISA; siRNA with RhoA activity assays and rescue in metastatic cells\",\n      \"pmids\": [\"30037999\", \"27392819\", \"29432180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanical stimulus source in vivo for EC cells not fully defined\", \"Generality of the RhoA axis across cancers unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified PIEZO2 as the bladder and baroreceptor mechanosensor and dissected Gβγ-dependent potentiation, broadening its physiological footprint and sensitization logic.\",\n      \"evidence\": \"Cell-type-specific conditional KO with cystometry and human genetics; Co-IP and electrophysiology for Nedd4-2; pharmacological PI3K/MAPK dissection with behavior\",\n      \"pmids\": [\"33057202\", \"33352230\", \"32227462\", \"32576830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nedd4-2 regulation shown by single-lab Co-IP/electrophysiology (Medium)\", \"Non-cell-autonomous skeletal role mechanism downstream of proprioceptive firing not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated PIEZO2 roles in voiding and ultrasonic hearing, showing it cooperates with other channels in non-canonical sensory contexts.\",\n      \"evidence\": \"Urothelial conditional KO with ATP-release assays; outer-hair-cell KO with audiometry and cochlear Ca2+ imaging\",\n      \"pmids\": [\"34464353\", \"34244441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIEZO2 integrates with conventional hair-cell mechanotransduction unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved polymodal force transmission and lipid/protein tuning, showing distinct mechanical stimuli engage distinct domains and regulators.\",\n      \"evidence\": \"IDR5 deletion with poking/stretch electrophysiology; TMEM120A and phosphatidic acid lipid regulation; PKA multi-site mutagenesis; coarse-grained MD simulation of lipid enrichment\",\n      \"pmids\": [\"35292651\", \"35819364\", \"37146970\", \"39147733\", \"35861699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid enrichment from MD is computational only, no experimental validation (Low, #43)\", \"How PA/TMEM120A regulation operates in vivo across tissues incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined voltage block as a tunable pain gate and identified trafficking and expression regulators, connecting channel availability and biophysics to mechanical pain.\",\n      \"evidence\": \"R2756 knock-in mice with electrophysiology and behavior; TMC7 and EndoA2/KIF5B Co-IP, conditional KO and rescue; vincristine/actin-tension pharmacology; YTHDF1 m6A regulation of PIEZO2 translation in cardiac fibroblasts\",\n      \"pmids\": [\"38984717\", \"38568807\", \"38475827\", \"37655331\", \"39498803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A/YTHDF1 control of PIEZO2 shown in single tissue context (Medium)\", \"EndoA2/TMC7 effects validated largely in one lab each\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PIEZO2 to metabolic organ crosstalk, showing fat-innervating PIEZO2 neurons shape adipose transcriptional programs.\",\n      \"evidence\": \"Neuron-specific conditional KO and gain-of-function mutant mice with adipose single-cell transcriptomics\",\n      \"pmids\": [\"40054462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanical stimulus sensed in fat not identified\", \"Causal signaling from PIEZO2 activation to adipose program not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct force-transmission pathways (membrane tension versus cytoskeleton via IDR5), lipid microenvironment, and the full set of accessory proteins integrate to produce tissue-specific gating thresholds remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified high-resolution structure of gated/lipid-bound states in corpus\", \"In vivo relevance of many regulators tested only heterologously\", \"Mechanism converting channel activity to downstream transcriptional/secretory programs incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 5, 20]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 4, 5, 18, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 20, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [4, 5, 8, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 22, 32]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 8, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"Mtmr2\", \"Nedd4-2\", \"TMC7\", \"EndoA2\", \"KIF5B\", \"Pericentrin\", \"TMEM120A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}