Caveolin-1 Assembles Type 1 Inositol 1,4,5-Trisphosphate Receptors and Canonical Transient Receptor Potential 3 Channels into a Functional Signaling Complex in Arterial Smooth Muscle Cells^*

Adebowale Adebiyi, Damodaran Narayanan, , and Jonathan H. Jaggar¹

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

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Abstract: Physical coupling of sarcoplasmic reticulum (SR) type 1 inositol 1,4,5-trisphosphate receptors (IP₃R1) to plasma membrane canonical transient receptor potential 3 (TRPC3) channels activates a cation current (I_Cat) in arterial smooth muscle cells that induces vasoconstriction. However, structural components that enable IP₃R1 and TRPC3 channels to communicate locally are unclear. Caveolae are plasma membrane microdomains that can compartmentalize proteins. Here, we tested the hypothesis that caveolae and specifically caveolin-1 (cav-1), a caveolae scaffolding protein, facilitate functional IP₃R1 to TRPC3 coupling in smooth muscle cells of resistance-size cerebral arteries. Methyl-β-cyclodextrin (MβCD), which disassembles caveolae, reduced IP₃-induced I_Cat activation in smooth muscle cells and vasoconstriction in pressurized arteries. Cholesterol replenishment reversed these effects. Cav-1 knockdown using shRNA attenuated IP₃-induced vasoconstriction, but did not alter TRPC3 and IP₃R1 expression. A synthetic peptide corresponding to the cav-1 scaffolding domain (CSD) sequence (amino acids 82–101) also attenuated IP₃-induced I_Cat activation and vasoconstriction. A cav-1 antibody co-immunoprecipitated cav-1, TRPC3, and IP₃R1 from cerebral artery lysate. ImmunoFRET indicated that cav-1, TRPC3 channels and IP₃R1 are spatially co-localized in arterial smooth muscle cells. IP₃R1 and TRPC3 channel spatial localization was disrupted by MβCD and a CSD peptide. Cholesterol replenishment re-established IP₃R1 and TRPC3 channel close spatial proximity. Taken together, these data indicate that in arterial smooth muscle cells, cav-1 co-localizes SR IP₃R1 and plasma membrane TRPC3 channels in close spatial proximity thereby enabling IP₃-induced physical coupling of these proteins, leading to I_Cat generation and vasoconstriction.

Key Words: Caveolae • Plasma Membrane • Sarcoplasmic Reticulum • Smooth Muscle • TRP Channels • IP3 Receptors

Received for publication August 27, 2010. Revision received October 23, 2010.

¹ To whom correspondence should be addressed: 894 Union Ave., Memphis TN 38163. Tel.: 901-448-1208; Fax: 901-448-7126; E-mail: jjaggar{at}uthsc.edu.

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