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J. Biol. Chem. 286 (6): 4341-4348

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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

ABSTRACT Back to Top

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 (ICat) 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 ICat 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 ICat 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 ICat 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}

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