Inositol trisphosphate and diacylglycerol as intracellular second messengers in liver

Receptor occupation by a variety of Ca²⁺-mobilizing hormones, such as α₁-adrenergic agents, vasopressin and angiotensin II, causes a rapid phosphodiesterase-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate in the plasma membrane with the production of the water soluble compound myo-inositol-1,4,5-trisphosphate (IP₃) and the lipophilic molecule 1,2-diacylglycerol (DG). This review summarizes the recent evidence obtained in the liver that defines the roles of these products as intracellular messengers of hormone action. Intracellular Ca²⁺ mobilization is mediated by IP₃, which releases Ca²⁺ from a subpopulation of the endoplasmic reticulum, resulting in a rapid increase of the cytosolic free Ca²⁺ concentration ([Ca²⁺](i)). Further effects of receptor occupancy are inhibition of the plasma membrane Ca²⁺-ATPase, despite net Ca²⁺ efflux, and an increased permeability of the plasma membrane to extracellular Ca²⁺. The activation of the phospholipid-dependent protein kinase C by DG does not alter Ca²⁺ fluxes across the plasma membrane. In contrast to some secretory cells, a synergism between protein kinase C activation and increased [Ca²⁺](i) is not observed in liver. Activation of protein kinase C profoundly inhibits the response to α₁-adrenergic agonists, with only minimal effects on the vasopressin response. It is concluded that in liver the two inositol-lipid messenger systems, IP₃ and DG, exert their effects by essentially separate pathways.