fig1

Figure 1. Schematic presentation of the mechanisms by which G protein-coupled receptors (GPCRs) regulate vascular tone and vascular smooth muscle cells (VSMC) proliferation. Vasoconstrictors like Ang II, ET1, thrombin, activate Gα_i, Gα_q, or G_12/13-coupled GPCRs, increase Ca²⁺ via PLCβ activity, and receptor operated calcium channels such as TRPC6. Increase in PLCβ activity decreases PIP2 relieving tonic inhibition of TRPC6. Increase in Erk1/2 activity by G_i/G_q-coupled GPCRs activates TRPC6 by phosphorylation leading to increased Ca²⁺ entry and calmodulin-dependent protein kinase (CAMK) activation. CAMK increases MLCK activity by phosphorylation, which in turn phosphorylates MLC phosphorylation causing vasoconstriction. GPCRs coupled to G_12/13 increase RhoA activity and the downstream kinase ROCK. ROCK increases MLC phosphorylation by inhibiting MLCP, or by direct phosphorylation. Vasodilators, such as PGI₂ acting via G_s-coupled receptors activate PKA thereby inhibit Ca²⁺ increase by PKA-mediated phosphorylation of PLCβ and TRPC6. In ECs, G_i, or G_q-coupled GPCRs, increase, PI3K-Akt signaling and activate eNOS by phosphorylation at Ser¹¹⁷⁷. NO diffuses to nearby VSMC, activating soluble guanylate cyclase, increasing cGMP, activating PKG, and inhibiting TRPC6 by phosphorylation. PKG also activates the GAPs for G_q, RGS2 and RGS4 to inhibit PLCβ activity thereby attenuating Ca²⁺ entry. Both PKG- and PKA inhibit RhoA by direct phosphorylation and promote vasodilation