Although inositol trisphosphate receptors (IP3Rs) are best known for their roles in releasing calcium from intracellular stores in response to IP3, in cells that have close apposition of the endoplasmic or sarcoplasmic reticulum (ER/SR) to the plasma membrane, IP3Rs can also influence the influx of extracellular calcium. This action of IP3 as a regulator of extracellular calcium currents is important for regulation of vasoconstriction and vascular tone through an IP3-induced cation current (ICat) that results from an interaction between ER/SR IP3Rs and surface-localized transient receptor potential 3 (TRPC3) channels. Adebiyi et al. found that disruption of plasma membrane microdomains called caveolae, which are rich in cholesterol and associated with the scaffolding protein caveolin, reduced ICat, myogenic tone, and IP3-induced vasoconstriction of isolated rat cerebral artery smooth muscle cells or arterial preparations. Knockdown of caveolin-1 or introduction of a peptide corresponding to the caveolin-1 scaffolding domain (CSD) also caused impairment of vascular responses similar to those observed by chemical disruption of caveolae. Coimmunoprecipitation experiments revealed that IP3R, TRPC3, and caveolin-1 were all present in a complex, and fluorescence resonance energy transfer (FRET) experiments showed that TRPC3 and caveolin-1 were in close proximity and that IP3R and TRPC3 were in close proximity. FRET between IP3R and TRPC3 was reduced by either chemical disruption of caveolae or introduction of the CSD peptide, consistent with the model that caveolin mediates the interaction of these two calcium channels at caveolae.
A. Adebiyi, D. Narayanan, J. H. Jaggar, 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. J. Biol. Chem. 286, 4341–4348 (2011). [Abstract] [Full Text]