Stimulus-secretion coupling in exocrine glands: the role of inositol-1,4,5-trisphosphate, calcium and cAMP

Abstract

Enzyme, electrolyte and fluid secretion from exocrine glands is stimulated by neurotransmitters and peptide hormones. Whereas for some of these secretagogues calcium is an important intracellular messenger, for others it is cyclic AMP. Regulation of steady state free Ca2+ concentration at rest and at stimulation have been studied in isolated permeabilized acinar cells from pancreas, parotid and lacrimal glands by measuring the free Ca2+ concentration of the surrounding incubation medium with a Ca2+-specific macroelectrode. Ca2+ transport mechanisms have been further characterized in subcellular membrane fractions by measuring 45Ca2+ uptake into membrane vesicles from rough endoplasmic reticulum (RER) and plasma membranes (PM). The data show that the intracellular messenger for secretagogue-induced Ca2+ release from RER is inositol-1,4,5-trisphosphate (IP3) which is produced during stimulation by phospholipase C mediated hydrolysis of phosphatidylinositol-bisphosphate. At rest both Ca2+ uptake into RER and Ca2+ extrusion from the cell is promoted by (Ca2+ + Mg2+)-ATPases with different characteristics in both types of membranes and by a coupled Na+/Ca2+ countertransport in the PM which keep cytosolic free Ca2+ concentration at a low level of approximately 2 - 4 X 10(-7) mol/l. During stimulation the Ca2+ permeability of endoplasmic reticulum membrane increases via IP3 and that of the PM by a yet unknown "receptor-operated" mechanism. These events lead to increase in cytosolic free Ca2+ concentration that is a trigger for enzyme, electrolyte and fluid secretion.