Fig. 6.

Mechanism of TGR5-mediated muscle relaxation. In gastric smooth muscle TGR5 receptors are coupled to stimulation of Gs and cAMP formation. Activation of TGR5 receptors leads to inhibition of RhoA/Rho kinase-mediated sustained contraction. The mechanism of inhibition involves PKA-dependent phosphorylation of RhoA at Ser¹⁸⁸ and PKA-independent, cAMP/Epac-dependent activation of Rap1. Both phosphorylation of RhoA and activation of Rap1 causes inhibition of Rho kinase activity leading to stimulation of MLCP activity and muscle relaxation.