Affinage

PKD2

Polycystin-2 · UniProt Q13563

Length
968 aa
Mass
109.7 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PKD2 encodes polycystin-2 (TRPP2), a Ca2+-permeable nonselective cation channel with six transmembrane spans and intracellular N- and C-termini that operates across multiple cellular compartments to transduce mechanical and chemical signals into Ca2+ flux (PMID:8650545, PMID:27071085). Its defining partnership is with PKD1 (polycystin-1): the two associate through C-terminal coiled-coil interactions, with the TRPP2 C-terminus forming a homotrimer that binds a single PKD1 coiled-coil to build a 1:3 (PKD1:TRPP2) complex, an arrangement resolved by cryo-EM as a domain-swapped, noncanonical TRP architecture (PMID:9192675, PMID:19556541, PMID:30093605). Channel assembly is further organized by a Cys632 extracellular disulfide and the C-terminal coiled-coil, and disrupting these abolishes homodimerization and complex formation (PMID:20168298, PMID:21474446). Beyond PKD1, TRPP2 assembles into homotetramers and heteromeric channels with TRPC1, TRPV4, and TRPM3, each with distinct conductance and permeation properties, and these complexes mediate flow-induced Ca2+ influx in endothelium and ciliary mechanosensation (PMID:18323855, PMID:19850920, PMID:19193631, PMID:20682256, PMID:25114176, PMID:30883612). TRPP2 localization—ER, basolateral plasma membrane, or primary cilium—is set by a C-terminal acidic-cluster signal whose CK2-dependent phosphorylation at Ser812 controls PACS adaptor binding and routing, and these compartments correspond to distinct functions: ER-localized TRPP2 lowers luminal Ca2+ to limit IP3R-mediated release and apoptosis and binds BECN1 to drive autophagy, while plasma-membrane channels carry mechanosensitive and EGF/PLC/PI3K-activated cation currents (PMID:10497221, PMID:15692563, PMID:16135816, PMID:19153608, PMID:32543276, PMID:18417723). Channel gating is tuned by PKA, PKD, and CK2 phosphorylation of the C-terminus and by SUMO1 modification that controls surface density in arterial myocytes (PMID:20881056, PMID:26269590, PMID:31822608), and biogenesis depends on N-glycosylation and PRKCSH/glucosidase-II-mediated glycan trimming that protect TRPP2 from ER-associated degradation (PMID:19801576, PMID:24719335). In vascular smooth muscle and endothelium, pressure- and flow-activated PKD2 channels control myogenic tone, eNOS-dependent vasodilation, and blood pressure (PMID:32364494, PMID:30511640), and in cilia the TRPP2-dependent channel directs left-right axis determination through Pkd1l1 (PMID:21307093, PMID:21307098). Somatic biallelic inactivation of Pkd2 in renal tubular cells is necessary and sufficient for cyst formation, establishing a cellular recessive two-hit mechanism for autosomal dominant polycystic kidney disease (PMID:9568711).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Established the molecular identity of PKD2 as a membrane protein, framing it as a candidate channel rather than an unknown disease gene.

    Evidence Positional cloning and sequence analysis revealing six transmembrane spans and similarity to voltage-gated Ca2+ channels

    PMID:8650545

    Open questions at the time
    • Sequence prediction alone did not demonstrate channel activity
    • No subcellular localization or partner identified
  2. 1997 High

    Defined the central PKD1-PKD2 partnership and the C-terminal coiled-coil that mediates it, explaining why mutations in either gene cause the same disease.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and in vitro binding mapping the interacting C-terminal tails

    PMID:9192675

    Open questions at the time
    • Stoichiometry of the complex not resolved
    • Functional consequence for channel activity not tested
  3. 1998 High

    Demonstrated the cellular genetic basis of ADPKD, showing cyst formation follows a recessive two-hit loss of Pkd2 within tubular cells.

    Evidence Mouse unstable-allele genetics with intragenic recombination and Pkd2 immunohistochemistry in cysts

    PMID:9568711

    Open questions at the time
    • Downstream signaling driving cyst growth not defined
    • Cell-of-origin timing not addressed
  4. 1999 High

    Localized polycystin-2 predominantly to the ER and identified the C-terminal retention signal, raising the question of how it reaches the plasma membrane and cilium.

    Evidence Immunofluorescence, fractionation, Endo H sensitivity, biotinylation, and truncation mutagenesis

    PMID:10497221

    Open questions at the time
    • Identity of the ER-binding partner unresolved at this stage
    • Mechanism of regulated export not known
  5. 2005 High

    Showed that compartmental routing is actively regulated by CK2 phosphorylation of Ser812 and PACS adaptor binding, providing a switch between ER, Golgi, and plasma membrane pools.

    Evidence Co-IP, phosphorylation assays, Ser812Ala mutagenesis, fractionation, and electrophysiology

    PMID:15692563

    Open questions at the time
    • Upstream signals controlling CK2 activity on PKD2 not defined
    • How routing couples to physiological demand unclear
  6. 2008 Medium

    Linked subcellular localization to distinct physiological outputs, showing ER-trapped versus plasma-membrane TRPP2 rescue different defects.

    Evidence Ser812Ala/Ser812Asp mutagenesis with zebrafish rescue of left-right asymmetry versus cyst phenotypes

    PMID:18417723

    Open questions at the time
    • Molecular effectors at each compartment not fully mapped
    • Quantitative partitioning between pools in native cells unknown
  7. 2009 High

    Resolved the architecture of the PKD1-PKD2 complex as a 3:1 trimer-of-TRPP2 binding one PKD1, defining the assembly rule for the complex.

    Evidence Crystallography of the TRPP2 C-terminal coiled-coil, single-molecule subunit counting, and mutagenesis

    PMID:19556541

    Open questions at the time
    • Full transmembrane architecture not resolved at this stage
    • Gating mechanism of the assembled complex unknown
  8. 2009 Medium

    Established a direct ER function for TRPP2 in lowering luminal Ca2+ to counteract SERCA and limit apoptotic Ca2+ release.

    Evidence Ca2+ imaging, RNAi knockdown, apoptosis assays, and pharmacology in renal epithelial cells

    PMID:19153608

    Open questions at the time
    • Direct demonstration of TRPP2 as the ER Ca2+ conductance not fully isolated from partners
    • Relationship to cyst pathology not established
  9. 2010 High

    Dissected multiple homo-oligomerization determinants (C-terminal coiled-coil, Cys632 disulfide) and separated complex assembly from intrinsic ER Ca2+-release function.

    Evidence Mutagenesis, co-IP, non-reducing SDS-PAGE, electrophysiology, and zebrafish phenotyping

    PMID:20168298 PMID:21474446

    Open questions at the time
    • Hierarchy of the three oligomerization domains in native assembly unclear
    • How disulfide formation is regulated unknown
  10. 2013 High

    Expanded the channel repertoire by showing TRPP2 forms functionally distinct heteromers with TRPC1, TRPV4, and TRPM3, accounting for diverse native channel properties.

    Evidence Co-IP, AFM, FRET, and single-channel electrophysiology across cell types (consolidated 2008-2014 plus ciliary studies)

    PMID:18323855 PMID:19193631 PMID:20682256 PMID:23977387 PMID:25114176 PMID:30883612

    Open questions at the time
    • Tissue-specific partner selection rules not defined
    • In vivo contribution of each heteromer not fully separated
  11. 2016 High

    Characterized the native ciliary TRPP2-dependent channel and key pore residues, defining its permeation and gating properties directly in cilia.

    Evidence Direct ciliary patch-clamp, CRISPR/Cas9 knockout, and structure-guided pore mutagenesis (D643, S4-S5 linker)

    PMID:27071085 PMID:27760766

    Open questions at the time
    • Physiological activating stimulus of the ciliary channel debated
    • Coupling between ciliary Ca2+ and downstream effectors incompletely mapped
  12. 2018 High

    Provided atomic-level architecture of the human PKD1-PKD2 complex, revealing a noncanonical TRP fold and features that may restrict cation permeation.

    Evidence Cryo-EM of the PKD1-PKD2 complex at 3.6 Å

    PMID:30093605

    Open questions at the time
    • Structure captured a closed/non-conducting state
    • Mechanism of physiological gating not visualized
  13. 2018 High

    Defined PKD2's role in vascular control, showing pressure- and adrenoceptor-activated smooth muscle channels and SUMO-regulated surface trafficking set blood pressure.

    Evidence Inducible cell-specific Pkd2 knockout mice, SUMO assays, patch-clamp, pressure myography, and blood pressure telemetry

    PMID:30511640 PMID:31822608

    Open questions at the time
    • SUMO ligase/protease acting on PKD2 not identified
    • Relationship between vascular and renal functions in ADPKD unresolved
  14. 2020 High

    Identified the activating ligand for the polycystin channel and an endothelial signaling output, linking complex gating to vasodilation.

    Evidence PC-1/PC-2 reconstitution with the soluble PC-1 N-terminal fragment agonist; EC-specific Pkd2 knockout with eNOS phosphorylation and blood pressure readouts

    PMID:32364494 PMID:33164752

    Open questions at the time
    • Physiological trigger for autoproteolytic fragment release unclear
    • Generality of the agonist across compartments not established
  15. 2020 Medium

    Connected TRPP2 Ca2+ channel activity to autophagy through a Ca2+-dependent BECN1 interaction, extending its function beyond ion conduction.

    Evidence Co-IP, CC1/D509V channel-dead mutagenesis, autophagy assays, and BAPTA-AM Ca2+ chelation

    PMID:32543276

    Open questions at the time
    • Compartment where the PKD2-BECN1 complex forms not pinpointed
    • Relevance to cyst pathology not tested in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple PKD2 channel assemblies and compartmental functions are coordinated in vivo, and which is the disease-relevant conductance driving cystogenesis, remains unresolved.
  • No unifying model linking ER, plasma-membrane, and ciliary PKD2 functions to cyst initiation
  • Physiological gating stimulus for the native polycystin complex not defined
  • Partner-selection logic across tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005929 cilium 4 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-9612973 Autophagy 1
Partners
BECN1EGFRPKD1PKD1L1PRKCSHTRPC1TRPM3TRPV4
Complex memberships
PKD1-PKD2 (polycystin) complexTRPP2-TRPC1 channelTRPP2-TRPM3 ciliary channelTRPP2-TRPV4 channel

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PKD2 encodes a predicted 968-amino acid integral membrane protein with six transmembrane spans, intracellular amino- and carboxyl-termini, similarity to voltage-activated calcium channels, and a potential calcium-binding domain. Positional cloning, sequence analysis Science High 8650545
1997 PKD1 and PKD2 proteins interact through their C-terminal cytoplasmic tails; the PKD2 C-terminal cytoplasmic tail forms homodimers through a coiled-coil domain distinct from the PKD1 interaction region; PKD1-PKD2 interaction upregulates PKD1 expression. Yeast two-hybrid, co-immunoprecipitation, in vitro binding Proceedings of the National Academy of Sciences of the United States of America High 9192675
1998 Somatic inactivation (loss of both alleles) of Pkd2 is necessary and sufficient for renal cyst formation in mice, establishing a cellular recessive (two-hit) mechanism for ADPKD type 2. Mouse genetics — unstable allele with intragenic homologous recombination, immunohistochemistry for Pkd2 expression in cysts Cell High 9568711
1999 Polycystin-2 is an ~110-kDa integral membrane glycoprotein that localizes predominantly to the endoplasmic reticulum in native tissues and cultured cells. A 34-amino acid region (Glu787–Ser820) in the C-terminal tail is responsible for exclusive ER retention and mediates interaction with an unidentified ER-binding partner; truncation at or before Glu787 allows plasma membrane trafficking. Immunofluorescence, co-localization with PDI/calnexin, subcellular fractionation, Endo H sensitivity, cell-surface biotinylation, truncation mutagenesis The Journal of biological chemistry High 10497221
1999 PKD2 protein directly associates with TRPC1 (but not TRPC3) via two distinct domains: a 73-amino acid region in the C-terminal cytoplasmic tail and a more N-terminal domain within transmembrane segments S2–S5 including the putative pore region. Co-immunoprecipitation in transfected cells and in vitro binding assay, deletion mutagenesis Proceedings of the National Academy of Sciences of the United States of America Medium 10097141
2000 PKD2 interacts with Hax-1 (a protein associated with the actin cytoskeleton) via its C-terminal domain, and Hax-1 associates with the F-actin-binding protein cortactin, providing a molecular link between PKD2 and the actin cytoskeleton. PKD2 and Hax-1 co-localize in the cell body and in cellular processes/lamellipodia. Yeast two-hybrid screen, immunofluorescence co-localization Proceedings of the National Academy of Sciences of the United States of America Low 10760273
2000 Polycystin-2 localizes to the basolateral plasma membrane of kidney tubular epithelial cells in vivo, distinct from the junctional localization of polycystin-1, suggesting independent as well as overlapping functions. Immunohistochemistry and immunofluorescence microscopy of human and murine renal tissues Journal of the American Society of Nephrology : JASN Medium 10770959
2004 PKD2 interacts with mDia1 (a RhoA GTPase-binding formin) via the PKD2 C-terminus binding to the mDia1 N-terminus. This interaction localizes PKD2 to mitotic spindles in dividing cells; RNAi knockdown of mDia1 causes loss of PKD2 from spindles and alters intracellular Ca2+ release. Yeast two-hybrid, co-immunoprecipitation in native and transfected cells, immunofluorescence, RNAi knockdown, Ca2+ imaging The Journal of biological chemistry Medium 15123714
2005 PKD2 (TRPP2) subcellular localization and trafficking are regulated by phosphofurin acidic cluster sorting proteins PACS-1 and PACS-2, which bind an acidic cluster in the PKD2 C-terminal domain. This binding is regulated by casein kinase 2-mediated phosphorylation (at Ser812), directing PKD2 routing between ER, Golgi, and plasma membrane. Co-immunoprecipitation, phosphorylation assays, subcellular fractionation, mutagenesis (Ser812Ala), functional electrophysiology The EMBO journal High 15692563
2005 PKD2 functions as an EGF-activated plasma membrane cation channel. EGF activates PKD2 via PLC and PI3K signaling, independently of store depletion. PIP2 negatively regulates PKD2 channel activity. PKD2 physically interacts with PLC-γ2 and EGFR and co-localizes with EGFR and PIP2 in the primary cilium. Electrophysiology (whole-cell patch clamp), RNAi knockdown, PIP2/PIP3 pipette infusion, pharmacology, co-immunoprecipitation, immunofluorescence Molecular and cellular biology High 16135816
2007 In Chlamydomonas reinhardtii, CrPKD2 moves bidirectionally in the flagellar membrane and its flagellar entry and abundance require intraflagellar transport (IFT). Flagellar CrPKD2 increases fourfold during gametogenesis, and RNAi strains show defects in flagella-dependent mating, indicating PKD2 couples flagellar adhesion to Ca2+ signaling during mating. GFP live imaging, FRAP, IFT block experiments, RNAi, mating assays The Journal of cell biology Medium 17984324
2008 TRPP2 and TRPC1 assemble to form a heteromeric receptor-operated channel with a 2:2 stoichiometry and alternating subunit arrangement, exhibiting unique single-channel conductance, amiloride sensitivity, and ion permeability profiles distinct from either subunit alone. Endogenous TRPP2/TRPC1 activity occurs in kidney cells and both subunits co-localize at the primary cilium. Electrophysiology, co-immunoprecipitation from kidney membranes, gain/loss-of-function experiments, immunofluorescence, atomic force microscopy EMBO reports High 18323855 19850920
2009 ER-localized TRPP2 reduces the Ca2+ concentration in the ER by increasing ER Ca2+ permeability, thereby counteracting SERCA activity and reducing IP3R-mediated Ca2+ release. This protects cells from apoptosis; TRPP2 knockdown in renal epithelial cells increases ER Ca2+ release and augments apoptotic sensitivity. Ca2+ imaging, RNAi knockdown, apoptosis assays, pharmacology (thapsigargin, IP3R agonists) The EMBO journal Medium 19153608
2009 The TRPP2/PKD1 complex contains 3 TRPP2 and 1 PKD1 subunits. A newly identified coiled-coil domain in the TRPP2 C-terminus forms a homotrimer (confirmed by crystallography) that binds a single PKD1 C-terminal coiled-coil. Mutations disrupting the TRPP2 coiled-coil trimer abolish complex assembly and reduce surface expression of both proteins. Biochemistry, X-ray crystallography, single-molecule subunit counting in live cells (fluorescence), mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 19556541
2009 PKD2/TRPP2 forms homotetramers and heteromeric complexes with TRPC1 in a tetrameric configuration. In homomeric PC2 channels, four subconductance states follow staircase behavior that is pH- and voltage-dependent; low pH inhibits homomeric but not heteromeric PC2/TRPC1 complexes, demonstrating distinct functional properties between homo- and heteromeric assemblies. Single-channel electrophysiology, atomic force microscopy, kinetic analysis Human molecular genetics Medium 19193631
2010 A coiled-coil domain in the PKD2 C-terminus functions as an essential homodimerization domain required for PC1 binding but not for PKD2 self-oligomerization. Dimerization-defective PKD2 mutants cannot reconstitute PC1/PC2 complexes at the plasma membrane or ER-PM junctions but retain ER Ca2+-release channel function. Expression of these mutants in zebrafish produces cystic phenotype. Mutagenesis, co-immunoprecipitation, electrophysiology, zebrafish in vivo rescue The EMBO journal High 20168298
2010 TRPP2 interacts with TRPV4 (but not TRPA1 or TRPM8), forming a heterotetramer with 2:2 stoichiometry and alternating subunit arrangement, analogous to the TRPP2-TRPC1 heteromer. Co-immunoprecipitation, atomic force microscopy with antibody labeling Biophysical journal Medium 20682256
2010 Protein kinase D phosphorylates polycystin-2 at Ser801 in the C-terminus; this phosphorylation is stimulated by serum/EGF, is required for PKD2-mediated inhibition of cell proliferation, and for ATP-stimulated ER Ca2+ release. A pathogenic ADPKD mutation (S804N) abolishes Ser801 phosphorylation. Mutagenesis, in vitro kinase assay, Ca2+ imaging, cell proliferation assay, Western blot Molecular biology of the cell Medium 20881056
2010 PRKCSH binds the C-terminal domain of TRPP2 in the ER and inhibits HERP-mediated ubiquitination of TRPP2, protecting it from ER-associated degradation. Loss of PRKCSH leads to reduced TRPP2 levels and cyst formation in zebrafish. Co-immunoprecipitation, ubiquitination assay, zebrafish knockdown/rescue experiments Human molecular genetics Medium 19801576
2011 Pkd1l1 physically interacts with Pkd2 and both co-localize to cilia of the embryonic node. Pkd1l1 and Pkd2 point mutants phenocopy each other (right isomerism, failure to activate asymmetric gene expression), establishing Pkd1l1 as a Pkd2 binding partner required for L-R patterning downstream of nodal flow. Co-immunoprecipitation, immunofluorescence co-localization in node cilia, genetic epistasis (parallel mutant phenotyping) Development High 21307093 21307098
2011 The TRPP2/PKD1 C-terminal coiled-coil complex forms a novel di-trimer configuration (upstream trimer of three TRPP2 helices; downstream trimer of two TRPP2 and one PKD1 helix). Mutagenesis of critical interface positions abolishes heteromeric coiled-coil complex assembly in full-length proteins in cells. Computational docking based on crystal structure of TRPP2 coiled-coil trimer, mutagenesis, biochemical co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America Medium 21642537
2011 Cys632 in the PKD2 extracellular loop constitutes a third homodimerization domain via disulfide bond formation. Combined disruption of Cys632 and the C-terminal coiled-coil domain nearly abolishes homodimer formation and ER Ca2+ release, but C632A mutant retains ability to heterodimerize with PKD1. Mutagenesis, non-reducing SDS-PAGE, co-immunoprecipitation, Ca2+ imaging (ATP-stimulated ER Ca2+ release) The Journal of biological chemistry Medium 21474446
2013 TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal collecting duct principal cells. This channel is activated by EGF via EGFR tyrosine kinase signaling; loss of either subunit reduces the 23-pS channel activity. Patch-clamp electrophysiology, immunofluorescence, co-immunoprecipitation, shRNA knockdown PloS one Medium 23977387
2013 TRPP2 is expressed in cerebral artery smooth muscle cells, residing primarily (~88%) in the plasma membrane. TRPP2 mediates stretch-activated cation currents (ICat), and its knockdown reduces myogenic tone at intravascular pressures of 40–100 mmHg without altering depolarization-induced vasoconstriction. Arterial biotinylation, immunofluorescence, patch-clamp electrophysiology, RNAi knockdown, pressure myography The Journal of physiology Medium 23858011
2014 TRPV4, TRPC1, and TRPP2 assemble to form a heteromeric channel complex; all three subunits contribute to the ion permeation pore. This heteromeric channel mediates flow-induced Ca2+ influx in native vascular endothelial cells. Two-step co-immunoprecipitation, FRET, patch-clamp electrophysiology with pore-dead mutants, Ca2+ imaging FASEB journal Medium 25114176
2014 Native TRPP2 is N-glycosylated at five asparagines in the first extracellular loop. Glycosylation is required for efficient TRPP2 biogenesis; mutation of glycosylated asparagines severely reduces protein expression. Glucosidase II (GIIβ/PRKCSH) mediates glycan trimming of TRPP2, and impaired trimming reduces TRPP2 abundance. Mass spectrometry, mutagenesis, Western blot, pharmacological inhibition of lysosomal degradation, genetic (Prkcsh-/- mice) The Journal of biological chemistry High 24719335
2015 Trpp2 (together with Trpv4) mediates endocardial calcium responses to oscillatory flow and is required for klf2a mechanosensitive expression and heart valve morphogenesis in zebrafish. Absence of Trpp2 leads to valve defects. Live Ca2+ imaging, klf2a promoter reporter assay, morpholino knockdown in zebrafish, mathematical flow modeling Current biology : CB Medium 25959969
2015 Pkd2 localizes to primary cilia of radial glia cells (RGCs) in the brain ventricular epithelium; conditional ablation of Pkd2 disrupts planar cell polarity (PCP) development in RGCs and ependymal cells and impairs asymmetric localization of PCP protein Vangl2, implicating Pkd2 in mechanosensory-driven PCP establishment. Immunofluorescence, conditional Cre-lox knockout (Nestin-Cre;Pkd2flox/flox), double-heterozygous epistasis (Pkd1 × Vangl2) The Journal of neuroscience Medium 26245976
2015 PKA directly phosphorylates polycystin-2 at Ser829 in the C-terminus; this increases channel mean open time without altering single-channel conductance. The phosphorylation is reversed by alkaline phosphatase. A truncation at Arg742 or mutation S829A abolishes PKA-mediated channel activation. Lipid bilayer reconstitution, in vitro PKA phosphorylation, mutagenesis (S829A, R742X), electrophysiology The Journal of biological chemistry High 26269590
2016 A constitutively active gain-of-function TRPP2 mutant (S4-S5 linker/S5 domain) revealed that extracellular divalent ions (including Ca2+) inhibit monovalent ion permeation by directly blocking the TRPP2 channel pore, and that D643 (a negatively charged pore residue) is crucial for channel permeability. Mutagenesis scanning, electrophysiology, zebrafish rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 27071085
2016 The native TRPP2-dependent channel in murine renal primary cilia is a large-conductance cation channel (97–189 pS) permeable to K+, Ca2+, and Na+ with permeability ratios PK:PCa:PNa of 1:0.55:0.14. Open probability increases with membrane depolarization or elevated cytoplasmic Ca2+. CRISPR/Cas9 knockout of TRPP2 eliminates this channel current. Direct electrophysiology from isolated primary cilia, CRISPR/Cas9 gene editing American journal of physiology. Renal physiology High 27760766
2018 The cryo-EM structure of the human PKD1-PKD2 complex at 3.6 Å reveals a 1:3 (PKD1:PKD2) ratio with domain-swapped, noncanonical TRP channel architecture. PKD1 contains a VGIC fold; its S6 helix is broken into S6a (resembling pore helix 1) and S6b (with three positively charged cavity-facing residues that may block cation permeation). Additional resolved domains include a five-TM helix domain and a cytosolic PLAT domain in PKD1. Cryo-electron microscopy at 3.6 Å resolution Science High 30093605
2018 PKD2 channels in arterial smooth muscle cells are modified by SUMO1 at physiological intravascular pressures. SUMOylated PKD2 (SUMO-PKD2) recycles between intracellular compartments and the plasma membrane, while unmodified PKD2 is surface-resident. Intravascular pressure activates voltage-dependent Ca2+ influx that stimulates SUMO-PKD2 recycling to the surface; desumoylation eliminates pressure-activated INa and causes vasodilation. Cell-specific inducible Pkd2 knockout mice, SUMO modification assays, patch-clamp electrophysiology, pressure myography Proceedings of the National Academy of Sciences of the United States of America High 31822608
2018 SLC25A25, a Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier, acts downstream of TRPP2-mediated ciliary Ca2+ signals. Identified by a genome-wide forward genetic screen in Drosophila and validated in zebrafish left-right patterning, establishing an evolutionarily conserved link between TRPP2 ciliary signaling and mitochondrial metabolism. Genome-wide forward genetic screen (Drosophila), zebrafish targeted knockdown with left-right patterning readout PLoS biology Medium 30080851
2020 Intravascular flow activates endothelial PKD2 channels, leading to Ca2+ influx that activates SK/IK channels and eNOS phosphorylation at Ser1176, producing arterial hyperpolarization and vasodilation. EC-specific Pkd2 knockout elevates blood pressure without altering cardiac function or kidney anatomy. Inducible EC-specific Pkd2 knockout mice, patch-clamp electrophysiology, eNOS phosphorylation assay, pressure myography, blood pressure telemetry eLife High 32364494
2020 The heteromeric PC-1/PC-2 polycystin complex reconstituted in the plasma membrane functions as an outwardly rectifying channel. A soluble fragment generated from autoproteolytic cleavage of the PC-1 N-terminal extracellular domain acts as an intrinsic agonist that is necessary and sufficient for channel activation of both reconstituted and native ciliary polycystin channels. Reconstitution of PC-1/PC-2 complex in mammalian plasma membrane, electrophysiology, application of soluble PC-1 N-terminal fragment, ciliary patch-clamp eLife High 33164752
2020 PKD2 forms a protein complex with BECN1 (beclin-1) via the CC1 coiled-coil domain in the PKD2 C-terminus, inducing autophagy. This interaction depends on PKD2 Ca2+ channel activity; a channel-dead mutant (D509V) shows diminished BECN1 binding and fails to induce autophagy. Depletion of intracellular Ca2+ (BAPTA-AM) disrupts the PKD2-BECN1 complex and blocks starvation-induced autophagy. Co-immunoprecipitation, mutagenesis (CC1 deletion, D509V), autophagy assays (LC3 II/I, autophagosomes), BAPTA-AM Ca2+ chelation Autophagy Medium 32543276
2020 Chlamydomonas PKD2 targets and anchors mastigonemes (MST1 glycoprotein filamentous polymers) to the extracellular surface of cilia. PKD2-mastigoneme complexes connect to axonemal doublets 4 and 8; pkd2 mutant cilia lack mastigonemes and cells swim with reduced velocity, suggesting a mechanosensory role. Immunofluorescence, electron microscopy, genetic analysis of pkd2 mutants, motility assays The Journal of cell biology Medium 32348466
2019 The large-conductance TRPP2-dependent channel in renal primary cilia also requires TRPM3; pharmacological activation with the TRPM3 agonist pregnenolone sulfate greatly enhances channel activity, and the specific TRPM3 inhibitor isosakuranetin blocks the channel. CRISPR/Cas9 knockout of TRPM3 eliminates the ciliary channel without altering ciliary TRPP2 protein levels. Direct ciliary electrophysiology, pharmacology (pregnenolone sulfate, isosakuranetin), CRISPR/Cas9 knockout of TRPM3, Western blot PloS one Medium 30883612
2018 PKD2 channels in arterial smooth muscle cells are activated by intravascular pressure and α1-adrenoceptors, mediating an inward Na+ current that causes membrane depolarization and vasoconstriction. Inducible smooth muscle-specific PKD2 knockout lowers physiological blood pressure, reduces hypertension, and prevents pathological arterial remodeling. Inducible smooth muscle-specific Pkd2 knockout mice, patch-clamp electrophysiology, pressure myography, blood pressure telemetry eLife High 30511640
2022 Fission yeast Pkd2 (polycystin homolog) permeates calcium when the membrane is stretched. In vitro reconstitution in giant unilamellar vesicles demonstrated Ca2+ permeability upon hypoosmotic shock; in vivo, pkd2 temperature-sensitive and hypomorphic mutants reduced intracellular Ca2+ levels and diminished cytokinesis-associated Ca2+ spikes, establishing Pkd2 as a mechanosensitive Ca2+-permeable channel activated by membrane stretching. Cell-free expression/reconstitution in GUVs, Ca2+ imaging in mutant yeast cells, hypoosmotic shock experiments Molecular biology of the cell Medium 36200871
2008 The subcellular localization of TRPP2 determines its function: ER-localized TRPP2 (Ser812Asp, PACS-trapped) more effectively rescues left-right asymmetry defects in TRPP2-deficient zebrafish, while plasma membrane-directed TRPP2 (Ser812Ala) rescues cyst formation. This indicates that TRPP2 assumes distinct compartment-specific roles. PACS-binding mutagenesis (Ser812Ala, Ser812Asp), zebrafish knockdown/rescue experiments, immunofluorescence Journal of the American Society of Nephrology : JASN Medium 18417723
2003 Drosophila Pkd2 is required for directional sperm movement inside the female reproductive tract. Targeted disruption causes male sterility without affecting spermatogenesis; mutant sperm are motile but fail to enter female storage organs, demonstrating PKD2 cation channel function in sperm flagella for directed movement. Genetic disruption (targeted P-element excision), fertility assays, sperm motility analysis, immunolocalization Current biology : CB Medium 14680633
2004 Drosophila Pkd2 loss-of-function severely reduces visceral smooth muscle contractility, which is rescued by muscle-specific Pkd2 expression. Pkd2 genetically interacts with the ryanodine receptor to regulate skeletal muscle Ca2+ oscillation during excitation-contraction coupling; Pkd2 is haploinsufficient for normal smooth muscle contractility. Genetic loss-of-function, tissue-specific rescue (Gal4/UAS), pharmacological perturbation (ryanodine), genetic interaction analysis The Journal of biological chemistry Medium 14732716
2009 Conditional loss of Pkd2 causes beta-catenin upregulation, as well as increased axin2 and cMyc expression, in renal collecting duct cells. Pkd2-null immortalized collecting duct cells show aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis, linking PC2 loss to dysregulation of beta-catenin-dependent signaling. Cre-loxP conditional knockout, Western blot, immunofluorescence, tubulomorphogenesis assay Journal of the American Society of Nephrology : JASN Medium 19939939
2008 Polycystin-2 (TRPP2) channel activity in human syncytiotrophoblast apical membranes is rapidly and completely inhibited by reactive oxygen species (H2O2, tBHP) applied to the intracellular side (IC50 ~131 nM in native membranes), with inhibition mediated by targeting both membrane lipids (lipid peroxidation) and the channel protein itself. Lipid bilayer reconstitution, electrophysiology, TBARS measurement, catalase treatment Placenta Medium 18417208

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science (New York, N.Y.) 1178 8650545
1999 Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet (London, England) 448 10023895
1998 Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 446 9568711
1997 Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proceedings of the National Academy of Sciences of the United States of America 426 9192675
1999 Identification and characterization of polycystin-2, the PKD2 gene product. The Journal of biological chemistry 286 10497221
1999 Specific association of the gene product of PKD2 with the TRPC1 channel. Proceedings of the National Academy of Sciences of the United States of America 261 10097141
2018 Structure of the human PKD1-PKD2 complex. Science (New York, N.Y.) 221 30093605
2005 Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. The EMBO journal 199 15692563
2000 The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton. Proceedings of the National Academy of Sciences of the United States of America 160 10760273
2007 Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella. The Journal of cell biology 153 17984324
2009 Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proceedings of the National Academy of Sciences of the United States of America 152 19556541
2015 Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development. Current biology : CB 147 25959969
2012 Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Human mutation 146 22508176
2011 Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. Development (Cambridge, England) 145 21307093
2005 PKD2 functions as an epidermal growth factor-activated plasma membrane channel. Molecular and cellular biology 138 16135816
2011 Interferon-γ-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology 136 22204817
2008 Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO reports 133 18323855
2000 Cellular and subcellular distribution of polycystin-2, the protein product of the PKD2 gene. Journal of the American Society of Nephrology : JASN 126 10770959
2010 The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation. Disease models & mechanisms 117 20335443
2003 PKD2 cation channel is required for directional sperm movement and male fertility. Current biology : CB 117 14680633
2002 Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Human molecular genetics 109 12140187
2011 Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left-right axis. Development (Cambridge, England) 105 21307098
2002 Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development. The American journal of pathology 103 11891195
2014 TRPV4, TRPC1, and TRPP2 assemble to form a flow-sensitive heteromeric channel. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 101 25114176
2006 The versatile nature of the calcium-permeable cation channel TRPP2. EMBO reports 96 16880824
2009 TRPP2 channels regulate apoptosis through the Ca2+ concentration in the endoplasmic reticulum. The EMBO journal 93 19153608
2004 PKD2 interacts and co-localizes with mDia1 to mitotic spindles of dividing cells: role of mDia1 IN PKD2 localization to mitotic spindles. The Journal of biological chemistry 87 15123714
2012 PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-κB- and HDAC1-mediated expression and activation of uPA. Journal of cell science 85 22797919
2006 General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia. Development (Cambridge, England) 85 16943275
2012 Up-regulation of hypoxia inducible factor-1α by cobalt chloride correlates with proliferation and apoptosis in PC-2 cells. Journal of experimental & clinical cancer research : CR 83 22453051
1998 Identification of PKD2L, a human PKD2-related gene: tissue-specific expression and mapping to chromosome 10q25. Genomics 83 9878261
1997 Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). Genomics 82 9286709
2016 The native TRPP2-dependent channel of murine renal primary cilia. American journal of physiology. Renal physiology 74 27760766
2010 Atomic force microscopy reveals the alternating subunit arrangement of the TRPP2-TRPV4 heterotetramer. Biophysical journal 73 20682256
2010 Pkd1 and Pkd2 are required for normal placental development. PloS one 73 20862291
2009 The transient receptor potential channels TRPP2 and TRPC1 form a heterotetramer with a 2:2 stoichiometry and an alternating subunit arrangement. The Journal of biological chemistry 72 19850920
1999 Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. Journal of the American Society of Nephrology : JASN 71 10541293
2013 Smooth muscle cell transient receptor potential polycystin-2 (TRPP2) channels contribute to the myogenic response in cerebral arteries. The Journal of physiology 70 23858011
2008 The cellulase/hemicellulase system of the anaerobic fungus Orpinomyces PC-2 and aspects of its applied use. Annals of the New York Academy of Sciences 70 18378601
2015 Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN 69 26139440
2006 Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 69 16720597
2011 Critical role of TRPP2 and TRPC1 channels in stretch-induced injury of blood-brain barrier endothelial cells. Brain research 68 22192412
2010 A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes. The EMBO journal 67 20168298
2009 Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin. Journal of the American Society of Nephrology : JASN 67 19939939
2020 The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus. eLife 66 33164752
2022 PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression. Nature communications 60 35965273
2016 Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant. Proceedings of the National Academy of Sciences of the United States of America 60 27071085
2009 The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1. Human molecular genetics 58 19193631
2009 Function and regulation of TRPP2 at the plasma membrane. American journal of physiology. Renal physiology 58 19244406
2007 TRPP2 and autosomal dominant polycystic kidney disease. Biochimica et biophysica acta 56 17292589
2002 Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Current opinion in nephrology and hypertension 55 11981261
2013 TRPP2 and TRPV4 form an EGF-activated calcium permeable channel at the apical membrane of renal collecting duct cells. PloS one 51 23977387
2011 Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach. Proceedings of the National Academy of Sciences of the United States of America 51 21642537
2007 VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice. American journal of physiology. Cell physiology 50 17475663
2019 circ-PKD2 inhibits carcinogenesis via the miR-204-3p/APC2 axis in oral squamous cell carcinoma. Molecular carcinogenesis 49 31206208
2004 Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). European journal of human genetics : EJHG 49 14872199
2020 Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure. eLife 47 32364494
2015 Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 26245976
2002 Mechanism of activation of protein kinase D2(PKD2) by the CCK(B)/gastrin receptor. The Journal of biological chemistry 46 12058027
2016 Pancreatic Cysts in Autosomal Dominant Polycystic Kidney Disease: Prevalence and Association with PKD2 Gene Mutations. Radiology 45 27046073
2018 Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure. eLife 44 30511640
2016 Atypical calcium regulation of the PKD2-L1 polycystin ion channel. eLife 44 27348301
2009 Lysophosphatidylcholine activates a novel PKD2-mediated signaling pathway that controls monocyte migration. Arteriosclerosis, thrombosis, and vascular biology 44 19520973
1998 A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds. Journal of the American Society of Nephrology : JASN 43 9773786
2008 The subcellular localization of TRPP2 modulates its function. Journal of the American Society of Nephrology : JASN 42 18417723
2008 Centrosome overduplication and mitotic instability in PKD2 transgenic lines. Cell biology international 42 18725310
2005 Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2). Pflugers Archiv : European journal of physiology 42 15971078
2010 PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation. Human molecular genetics 41 19801576
2014 N-glycosylation determines the abundance of the transient receptor potential channel TRPP2. The Journal of biological chemistry 40 24719335
1997 Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene. Human genetics 37 9402976
2000 Distinct and common developmental expression patterns of the murine Pkd2 and Pkd1 genes. Mechanisms of development 36 10781953
2020 Chlamydomonas PKD2 organizes mastigonemes, hair-like glycoprotein polymers on cilia. The Journal of cell biology 35 32348466
2018 Exosome-delivered TRPP2 siRNA inhibits the epithelial-mesenchymal transition of FaDu cells. Oncology letters 35 30675260
2010 Protein kinase D-mediated phosphorylation of polycystin-2 (TRPP2) is essential for its effects on cell growth and calcium channel activity. Molecular biology of the cell 35 20881056
2001 Mutations of the human polycystic kidney disease 2 (PKD2) gene. Human mutation 35 11438989
2020 PKD2/polycystin-2 induces autophagy by forming a complex with BECN1. Autophagy 34 32543276
2016 TRPP2 Enhances Metastasis by Regulating Epithelial-Mesenchymal Transition in Laryngeal Squamous Cell Carcinoma. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 34 27832627
2010 Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 34 21115670
2004 Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility. The Journal of biological chemistry 34 14732716
2007 Overexpression of PKD2 in the mouse is associated with renal tubulopathy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 33 18048422
2014 Naringenin inhibits the growth of Dictyostelium and MDCK-derived cysts in a TRPP2 (polycystin-2)-dependent manner. British journal of pharmacology 32 24116661
2021 Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing. Journal of the American Society of Nephrology : JASN 31 34716216
2007 PKD1, PKD2, and their substrate Kidins220 regulate neurotensin secretion in the BON human endocrine cell line. The Journal of biological chemistry 31 18048355
2019 SUMO1 modification of PKD2 channels regulates arterial contractility. Proceedings of the National Academy of Sciences of the United States of America 30 31822608
2014 Increased TRPP2 expression in vascular smooth muscle cells from high-salt intake hypertensive rats: The crucial role in vascular dysfunction. Molecular nutrition & food research 29 25351462
2008 Submembraneous microtubule cytoskeleton: interaction of TRPP2 with the cell cytoskeleton. The FEBS journal 28 18754774
2022 Circ-PKD2 promotes Atg13-mediated autophagy by inhibiting miR-646 to increase the sensitivity of cisplatin in oral squamous cell carcinomas. Cell death & disease 27 35220397
2018 The mitochondrial transporter SLC25A25 links ciliary TRPP2 signaling and cellular metabolism. PLoS biology 27 30080851
2011 A single amino acid residue constitutes the third dimerization domain essential for the assembly and function of the tetrameric polycystin-2 (TRPP2) channel. The Journal of biological chemistry 27 21474446
2008 Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. European journal of clinical investigation 25 18257781
2008 Reactive oxygen species inhibit polycystin-2 (TRPP2) cation channel activity in term human syncytiotrophoblast. Placenta 25 18417208
2019 The TRPP2-dependent channel of renal primary cilia also requires TRPM3. PloS one 23 30883612
2019 Opening TRPP2 (PKD2L1) requires the transfer of gating charges. Proceedings of the National Academy of Sciences of the United States of America 23 31315976
2014 Role of PKD2 in rheotaxis in Dictyostelium. PloS one 23 24520414
2017 TRPP2 ion channels: Critical regulators of organ morphogenesis in health and disease. Cell calcium 22 28807147
2016 The functions of TRPP2 in the vascular system. Acta pharmacologica Sinica 21 26725733
2022 PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan. NPJ genomic medicine 20 35778421
2015 The cAMP Signaling Pathway and Direct Protein Kinase A Phosphorylation Regulate Polycystin-2 (TRPP2) Channel Function. The Journal of biological chemistry 20 26269590
2011 Differential expression of PKD1 and PKD2 in gastric cancer and analysis of PKD1 and PKD2 function in the model system. Experimental oncology 19 22217708
2022 Membrane stretching activates calcium permeability of a putative channel Pkd2 during fission yeast cytokinesis. Molecular biology of the cell 18 36200871

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