TY - JOUR
T1 - IP3 constricts cerebral arteries via IP3 receptor-mediated TRPC3 channel activation and independently of sarcoplasmic reticulum Ca2+ release
AU - Xi, Qi
AU - Adebiyi, Adebowale
AU - Zhao, Guiling
AU - Chapman, Kenneth E.
AU - Waters, Christopher M.
AU - Hassid, Aviv
AU - Jaggar, Jonathan H.
PY - 2008/5
Y1 - 2008/5
N2 - Vasoconstrictors that bind to phospholipase C-coupled receptors elevate inositol-1,4,5-trisphosphate (IP3). IP3 is generally considered to elevate intracellular Ca concentration ([Ca]i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP3 receptors, leading to intracellular Ca release. We show that IP3 also stimulates vasoconstriction via a SR Ca release-independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca was depleted to abolish Ca release (measured using D1ER, a fluorescence resonance energy transfer-based SR Ca indicator), IP3 activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (ICat) caused by Na influx, induced membrane depolarization, elevated [Ca]i, and stimulated vasoconstriction. The IP3-induced ICat and [Ca]i elevation were attenuated by cation channel (Gd, 2-APB) and IP3 receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca channel blockers, reduced the SR Ca release-independent, IP3-induced [Ca]i elevation and vasoconstriction. In pressurized arteries, SR Ca depletion did not alter IP3-induced constriction at 20 mm Hg but reduced IP3-induced constriction by ≈39% at 60 mm Hg. [Ca]i elevations and constrictions induced by endothelin-1, a phospholipase C-coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca-depleted arteries. In summary, we describe a novel mechanism of IP3-induced vasoconstriction that does not occur as a result of SR Ca release but because of IP3 receptor-dependent ICat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca channels, leading to a myocyte [Ca]i elevation, and vasoconstriction.
AB - Vasoconstrictors that bind to phospholipase C-coupled receptors elevate inositol-1,4,5-trisphosphate (IP3). IP3 is generally considered to elevate intracellular Ca concentration ([Ca]i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP3 receptors, leading to intracellular Ca release. We show that IP3 also stimulates vasoconstriction via a SR Ca release-independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca was depleted to abolish Ca release (measured using D1ER, a fluorescence resonance energy transfer-based SR Ca indicator), IP3 activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (ICat) caused by Na influx, induced membrane depolarization, elevated [Ca]i, and stimulated vasoconstriction. The IP3-induced ICat and [Ca]i elevation were attenuated by cation channel (Gd, 2-APB) and IP3 receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca channel blockers, reduced the SR Ca release-independent, IP3-induced [Ca]i elevation and vasoconstriction. In pressurized arteries, SR Ca depletion did not alter IP3-induced constriction at 20 mm Hg but reduced IP3-induced constriction by ≈39% at 60 mm Hg. [Ca]i elevations and constrictions induced by endothelin-1, a phospholipase C-coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca-depleted arteries. In summary, we describe a novel mechanism of IP3-induced vasoconstriction that does not occur as a result of SR Ca release but because of IP3 receptor-dependent ICat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca channels, leading to a myocyte [Ca]i elevation, and vasoconstriction.
KW - Endothelin-1
KW - TRPC channels
KW - Vascular smooth muscle
KW - Voltage-dependent calcium channels
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UR - http://www.scopus.com/inward/citedby.url?scp=43449098527&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.108.173948
DO - 10.1161/CIRCRESAHA.108.173948
M3 - Article
C2 - 18388325
AN - SCOPUS:43449098527
SN - 0009-7330
VL - 102
SP - 1118
EP - 1126
JO - Circulation Research
JF - Circulation Research
IS - 9
ER -