Figure 10.

Regulation of IP₃ receptors by vasoconstrictors and vasodilators. Schematic of the plasma membrane and the ER membrane of a vascular SMC showing, from left to right in the plasma membrane, a G_s-protein-coupled receptor, associated G-proteins and AC, a BK_Ca channel, a TRPC3 channel and a G_q-protein-coupled receptor (G_qPCR), associated G-proteins and phospholipase C-β (PLCβ), and an IP₃ receptor (IP₃R) in the membrane of the ER. Increases in IP₃ and moderate increases in cytoplasmic Ca²⁺ in the environment of an IP₃R are the primary stimulae for activation. Activation of IP₃Rs by cytosolic Ca²⁺ is mediated by direct actions of Ca²⁺ on the channels, or through activation of calcium-calmodulin-dependent protein kinase (CaMK) and phosphorylation of the channels. Vasoconstrictors acting through G_qPCRs and activation of PLCβ increase the production of IP₃, stimulating Ca²⁺ release through IP₃R. Activated IP₃Rs have been shown to physically interact with, and activate plasma membrane BK_Ca and TRPC3 channels, as shown. Conversely, high levels of intracellular Ca²⁺ inhibit IP₃R activity through mechanisms involving the Ca²⁺ binding protein, CaM. NO, through activation of soluble guanylate cyclase, increased production of cGMP and activation of PKG phosphorylates IRAG which inhibits IP₃R activity. Vasodilators that act at G_sPCRs (isoproterenol, adenosine, prostacyclin, CGRP, etc.), activate AC to increase producting of cAMP which then can activate PKA to phosphorylate IP₃Rs to decrease their activity. See text for more information.