Fig. 6. Contribution of TRPM3 channels to Ca²⁺ entry and insulin release in beta cells. Opening of TRPM3 channels after binding of the TRPM3 agonist pregnenolone sulfate promotes Ca²⁺ and Na⁺ influx and membrane depolarization which in turn triggers additional Ca²⁺ entry into the cell through verapamil-sensitive CaV channels resulting in the release of insulin. Glucose taken up by glucose transporters (GLUT) and metabolized in the cell increases the amount of ATP which blocks ATP-sensitive potassium (K⁺) channels (K_ATP channels). Their closure leads to membrane depolarization and the opening of CaVs. Independent of PS, glucose triggers TRPM3 activity conceivably via ATP-dependent activation of phosphatidylinositol-kinase (PI-Kinase), regeneration of phosphatidylinositol 4,5-bisphosphate (PIP₂), and direct PIP₂-mediated stimulation of TRPM3. TRPM3 activity is suppressed by direct interaction with Gβγ- subunits of G-protein coupled receptors (GPCR) as well as Ca²⁺/calmodulin (CaM).