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VASCULAR BIOLOGY

Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca²⁺ signals, and vasoconstriction in cerebral arteries

Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 10 July 2008 ; accepted in final form 12 September 2008

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) regulate diverse physiological functions, including contraction and proliferation. There are three IP₃R isoforms, but their functional significance in arterial smooth muscle cells is unclear. Here, we investigated relative expression and physiological functions of IP₃R isoforms in cerebral artery smooth muscle cells. We show that 2-aminoethoxydiphenyl borate and xestospongin C, membrane-permeant IP₃R blockers, reduced Ca²⁺ wave activation and global intracellular Ca²⁺ ([Ca²⁺]_i) elevation stimulated by UTP, a phospholipase C-coupled purinergic receptor agonist. Quantitative PCR, Western blotting, and immunofluorescence indicated that all three IP₃R isoforms were expressed in acutely isolated cerebral artery smooth muscle cells, with IP₃R1 being the most abundant isoform at 82% of total IP₃R message. IP₃R1 knockdown with short hairpin RNA (shRNA) did not alter baseline Ca²⁺ wave frequency and global [Ca²⁺]_i but abolished UTP-induced Ca²⁺ wave activation and reduced the UTP-induced global [Ca²⁺]_i elevation by 61%. Antibodies targeting IP₃R1 and IP₃R1 knockdown reduced UTP-induced nonselective cation current (I_cat) activation. IP₃R1 knockdown also reduced UTP-induced vasoconstriction in pressurized arteries with both intact and depleted sarcoplasmic reticulum (SR) Ca²⁺ by 45%. These data indicate that IP₃R1 is the predominant IP₃R isoform expressed in rat cerebral artery smooth muscle cells. IP₃R1 stimulation contributes to UTP-induced I_cat activation, Ca²⁺ wave generation, global [Ca²⁺]_i elevation, and vasoconstriction. In addition, IP₃R1 activation constricts cerebral arteries in the absence of SR Ca²⁺ release by stimulating plasma membrane I_cat.

cerebral artery smooth muscle cells; calcium wave; short hairpin RNA

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