{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:57:23Z","timestamp":1771261043017,"version":"3.50.1"},"reference-count":68,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T00:00:00Z","timestamp":1595289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/J007226\/1"],"award-info":[{"award-number":["BB\/J007226\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M018350\/1"],"award-info":[{"award-number":["BB\/M018350\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In vascular smooth muscle cells (VSMCs), activation of Ca<jats:sup>2+<\/jats:sup>\u2010permeable store\u2010operated channels (SOCs) composed of canonical transient receptor potential channel 1 (TRPC1) subunits mediates Ca<jats:sup>2+<\/jats:sup> entry pathways that regulate contraction, proliferation and migration, which are processes associated with vascular disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Activation of TRPC1\u2010based SOCs requires protein kinase C (PKC) activity, which is proposed to phosphorylate TRPC1 proteins to promote channel opening by phosphatidylinositol 4,5\u2010bisphosphate (PIP<jats:sub>2<\/jats:sub>). We investigated the identity of the PKC isoform involved in activating TRPC1\u2010based SOCs in rat mesenteric artery VSMCs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>TRPC1\u2010based SOCs were reduced by PKC\u03b4 inhibitors and knockdown of PKC\u03b4 expression. Store depletion induced interactions between TRPC1 and PKC\u03b4 and PKC\u03b4\u2010dependent phosphorylation of TRPC1. Furthermore, generation of store\u2010operated interactions between PIP<jats:sub>2<\/jats:sub> and TRPC1 and activation of TRPC1\u2010based SOCs by PIP<jats:sub>2<\/jats:sub> required PKC\u03b4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings reveal that PKC\u03b4 activity has an obligatory role in activating TRPC1\u2010based SOCs, through regulating PIP<jats:sub>2<\/jats:sub>\u2010mediated channel opening.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>In vascular smooth muscle cells (VMSCs), stimulation of Ca<jats:sup>2+<\/jats:sup>\u2010permeable canonical transient receptor potential channel 1 (TRPC1)\u2010based store\u2010operated channels (SOCs) mediates Ca<jats:sup>2+<\/jats:sup> entry pathways that regulate cell contraction, proliferation and migration, which are processes associated with vascular disease. It is therefore important to understand how TRPC1\u2010based SOCs are activated. Stimulation of TRPC1\u2010based SOCs requires protein kinase C (PKC) activity, with store\u2010operated PKC\u2010dependent phosphorylation of TRPC1 essential for channel opening by phosphatidylinositol 4,5\u2010bisphosphate (PIP<jats:sub>2<\/jats:sub>). Experimental protocols used to activate TRPC1\u2010based SOCs suggest that the PKC isoform involved requires diacylglycerol (DAG) but is Ca<jats:sup>2+<\/jats:sup>\u2010insensitive, which are characteristics of the novel group of PKC isoforms (\u03b4, \u03b5, \u03b7, \u03b8). Hence, the present study examined whether a novel PKC isoform(s) is involved in activating TRPC1\u2010based SOCs in contractile rat mesenteric artery VSMCs. Store\u2010operated whole\u2010cell cation currents were blocked by Pico145, a highly selective and potent TRPC1\/4\/5 channel blocker and T1E3, a TRPC1 blocking antibody. PKC\u03b4 was expressed in VSMCs, and selective PKC\u03b4 inhibitory peptides and knockdown of PKC\u03b4 expression with morpholinos oligomers inhibited TRPC1\u2010based SOCs. TRPC1 and PKC\u03b4 interactions and phosphorylation of TRPC1 induced by store depletion were both reduced by pharmacological inhibition and PKC\u03b4 knockdown. In addition, store\u2010operated PIP<jats:sub>2<\/jats:sub> and TRPC1 interactions were blocked by PKC\u03b4 inhibition, and PKC\u03b4 was required for PIP<jats:sub>2<\/jats:sub>\u2010mediated activation of TRPC1 currents. These results identify the involvement of PKC\u03b4 in stimulation of TRPC1\u2010based SOCs and highlight that store\u2010operated PKC\u03b4 activity is obligatory for channel opening by PIP<jats:sub>2<\/jats:sub>, the probable activating ligand.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279947","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T07:01:31Z","timestamp":1594018891000},"page":"3911-3925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Obligatory role for PKC\u03b4 in PIP<sub>2<\/sub>\u2010mediated activation of store\u2010operated TRPC1 channels in vascular smooth muscle cells"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9399-4013","authenticated-orcid":false,"given":"Miguel A. S.","family":"Mart\u00edn\u2010Arag\u00f3n Baudel","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of California  451, Health Sciences Drive, Suite 3503 Davis CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Shi","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine Faculty of Medicine and Health University of Leeds  Leeds UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5850-8005","authenticated-orcid":false,"given":"William A.","family":"Large","sequence":"additional","affiliation":[{"name":"Vascular Biology Research Centre Molecular and Clinical Research Institute St George's University of London  Cranmer Terrace London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-9634","authenticated-orcid":false,"given":"Anthony P.","family":"Albert","sequence":"additional","affiliation":[{"name":"Vascular Biology Research Centre Molecular and Clinical Research Institute St George's University of London  Cranmer Terrace London 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