title: An elevation in physical coupling of type 1 inositol 1,4,5-trisphosphate (IP3) receptors to transient receptor potential 3 (TRPC3) channels constricts mesenteric arteries in genetic hypertension.
abstract: Hypertension is associated with an elevation in agonist-induced vasoconstriction, but mechanisms involved require further investigation. Many vasoconstrictors bind to phospholipase C-coupled receptors, leading to an elevation in inositol 1,4,5-trisphosphate (IP(3)) that activates sarcoplasmic reticulum IP(3) receptors. In cerebral artery myocytes, IP(3) receptors release sarcoplasmic reticulum Ca(2+) and can physically couple to canonical transient receptor potential 3 (TRPC3) channels in a caveolin-1-containing macromolecular complex, leading to cation current activation that stimulates vasoconstriction. Here, we investigated mechanisms by which IP(3) receptors control vascular contractility in systemic arteries and IP(3)R involvement in elevated agonist-induced vasoconstriction during hypertension. Total and plasma membrane-localized TRPC3 protein was ≈2.7- and 2-fold higher in mesenteric arteries of spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto (WKY) rat controls, respectively. In contrast, IP(3)R1, TRPC1, TRPC6, and caveolin-1 expression was similar. TRPC3 expression was also similar in arteries of pre-SHRs and WKY rats. Control, IP(3)-induced and endothelin-1 (ET-1)-induced fluorescence resonance energy transfer between IP3R1 and TRPC3 was higher in SHR than WKY myocytes. IP3-induced cation current was ≈3-fold larger in SHR myocytes. Pyr3, a selective TRPC3 channel blocker, and calmodulin and IP(3) receptor binding domain peptide, an IP(3)R-TRP physical coupling inhibitor, reduced IP(3)-induced cation current and ET-1-induced vasoconstriction more in SHR than WKY myocytes and arteries. Thapsigargin, a sarcoplasmic reticulum Ca(2+)-ATPase blocker, did not alter ET-1-stimulated vasoconstriction in SHR or WKY arteries. These data indicate that ET-1 stimulates physical coupling of IP(3)R1 to TRPC3 channels in mesenteric artery myocytes, leading to vasoconstriction. Furthermore, an elevation in IP(3)R1 to TRPC3 channel molecular coupling augments ET-1-induced vasoconstriction during hypertension.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA.
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adebiyi
authors.forename: Candice M
authors.initials: CM
authors.lastname: Thomas-Gatewood
authors.forename: M Dennis
authors.initials: MD
authors.lastname: Leo
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kidd
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Neeb
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D050052:TRPC Cation Channels / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001896:Boron Compounds; D051242:Caveolin 1; D019332:Endothelin-1; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011720:Pyrazoles; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate; C109986:2-aminoethoxydiphenyl borate