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(Circulation Research. 2008;102:1118.)
© 2008 American Heart Association, Inc.

Integrative Physiology

IP₃ Constricts Cerebral Arteries via IP₃ Receptor–Mediated TRPC3 Channel Activation and Independently of Sarcoplasmic Reticulum Ca²⁺ Release

Qi Xi, Adebowale Adebiyi, Guiling Zhao, Kenneth E. Chapman, Christopher M. Waters, Aviv Hassid, Jonathan H. Jaggar

From the Department of Physiology, University of Tennessee Health Science Center, Memphis.

Correspondence to Jonathan H. Jaggar, University of Tennessee Health Science Center, Department of Physiology, 894 Union Ave, Nash Building, Memphis, TN 38139. E-mail jjaggar{at}physio1.utmem.edu

Vasoconstrictors that bind to phospholipase C–coupled receptors elevate inositol-1,4,5-trisphosphate (IP₃). IP₃ is generally considered to elevate intracellular Ca²⁺ concentration ([Ca²⁺]_i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP₃ receptors, leading to intracellular Ca²⁺ release. We show that IP₃ also stimulates vasoconstriction via a SR Ca²⁺ release–independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca²⁺ was depleted to abolish Ca²⁺ release (measured using D1ER, a fluorescence resonance energy transfer–based SR Ca²⁺ indicator), IP₃ activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (I_Cat) caused by Na⁺ influx, induced membrane depolarization, elevated [Ca²⁺]_i, and stimulated vasoconstriction. The IP₃-induced I_Cat and [Ca²⁺]_i elevation were attenuated by cation channel (Gd³⁺, 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 Ca²⁺ channel blockers, reduced the SR Ca²⁺ release–independent, IP₃-induced [Ca²⁺]_i elevation and vasoconstriction. In pressurized arteries, SR Ca²⁺ depletion did not alter IP₃-induced constriction at 20 mm Hg but reduced IP₃-induced constriction by 39% at 60 mm Hg. [Ca²⁺]_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 Ca²⁺-depleted arteries. In summary, we describe a novel mechanism of IP₃-induced vasoconstriction that does not occur as a result of SR Ca²⁺ release but because of IP₃ receptor–dependent I_Cat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca²⁺ channels, leading to a myocyte [Ca²⁺]_i elevation, and vasoconstriction.

Key Words: vascular smooth muscle • voltage-dependent calcium channels • TRPC channels • endothelin-1