{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["MacKay CE"],"funding":["American Heart Association","NHLBI NIH HHS","National Heart, Lung, and Blood Institute","Medical Research Council"],"pagination":["e74765"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8933003"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11"],"pubmed_abstract":["Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the <i>Pkd1</i> gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific <i>Pkd1</i> knockout (<i>Pkd1</i> ecKO) mice, we show that flow activates PC-1-mediated, Ca<sup>2+</sup>-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase (eNOS) and intermediate (IK)- and small (SK)-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (<i>Pkd2</i> ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (<i>Pkd1</i>/<i>Pkd2</i> ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates nonselective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility through the formation of an interdependent signaling complex with PC-2 in ECs. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to eNOS, IK channel, and SK channel activation, vasodilation, and a reduction in blood pressure."],"journal":["eLife"],"pubmed_title":["A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation."],"pmcid":["PMC8933003"],"funding_grant_id":["MR/M024962/1","R01 HL158846","HL149662","R01 HL019134","R01 HL133256","R01 HL149662","R01 HL137745","MC_EX_MR/N50192X/1","855946","HL137745","HL155180","Hl155186","HL133256","HL19134","R01 HL155180","20POST35210200"],"pubmed_authors":["Hasan R","Fernandez-Pena C","Leo MD","MacKay CE","Floen M","Singh P","Malik KU","Jaggar JH","Garrud TAC"],"additional_accession":[]},"is_claimable":false,"name":"A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation.","description":"Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the <i>Pkd1</i> gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific <i>Pkd1</i> knockout (<i>Pkd1</i> ecKO) mice, we show that flow activates PC-1-mediated, Ca<sup>2+</sup>-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase (eNOS) and intermediate (IK)- and small (SK)-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (<i>Pkd2</i> ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (<i>Pkd1</i>/<i>Pkd2</i> ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates nonselective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility through the formation of an interdependent signaling complex with PC-2 in ECs. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to eNOS, IK channel, and SK channel activation, vasodilation, and a reduction in blood pressure.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2026-06-04T04:35:46.291Z","creation":"2024-11-09T12:05:22.313Z"},"accession":"S-EPMC8933003","cross_references":{"pubmed":["35229718"],"doi":["10.7554/eLife.74765"]}}