New Insights Into Second Messenger Regulation Of Parietal Cell FunctionBy Novel Downstream Signaling Proteins

Abstract

HCl secretion by the gastric parietal cell is increased by independent activation of both the cAMP and calcium-dependent signaling pathways. The dramatic internal membrane rearrangements that accompany HCl secretion appear to involve an exocytotic process in which the H⁺,K⁺-ATPase, or proton pump, is translocated from cytoplasmic tubulovesicles to the canalicular membrane, whereupon it becomes active (16). It is well established that histamine binding to H2-type receptors activates adenylyl cyclase, increases [cAMPJi and activates cAMP-dependent protein kinase. In contrast, cholinergic agonists such as carbachol bind to muscarinic M3-type receptors and increase intracellular concentrations of inositol 1,3,5 trisphosphate, diaclyglycerol and [Ca²⁺]i (21,52). Although the downstream protein kinases in the cholinergic signaling pathway have not been unequivocally defined, most evidence supports the involvement of both calcium-dependent protein kinase(s) and protein kinase C (21,52). The activation of multiple protein kinases in the various signaling pathways predicts the involvement of multiple phosphoprotein substrates. To date, two regulated phosphoproteins have been identified in the cAMP signaling pathway, ezrin and lasp-1 (11,20). Two other proteins, CSPP28 and coroninsc, have been identified as calcium and protein kinase C-dependent phosphoproteins, respectively (38,39). The identification of these new signaling proteins has generated many more questions. Which cellular activities are modified by changes in protein phosphorylation? Are other phosphoproteins also regulated within these signaling pathways? Do the pathways intersect? If so, where? Our goal has been to address these questions systematically by 1) identifying the regulated phosphoproteins and 2) applying a wide range of molecular and physiological approaches to characterize these proteins.