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© 2001 by the American Diabetes Association, Inc.
Protein Kinase C and Calcium Regulation of Adenylyl Cyclase in Isolated Rat Pancreatic Islets
Department of Pharmacology and Toxicology, the State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York
Rat islets express several isoforms of adenylyl cyclase (AC), and the regulation of AC activity in isolated islets by Ca2+ and protein kinase C (PKC) was investigated. At basal 2.8 mmol/l glucose, the muscarinic receptor agonist carbamylcholine chloride (CCh) evoked a concentration-dependent increase in cAMP generation with a maximum increase at least 4.5-fold above control. In contrast, forskolin and glucagon-like peptide 1 fragment 7-36 amide increased cAMP accumulation 23-fold and almost 10-fold, respectively. Cholecystokinin 26-33 sulfated amide (CCK) also stimulated cAMP production by up to eightfold, as did the phorbol ester, phorbol 12,13-dibutyrate (PDBu). PDBu and CCh or CCK responses were not additive. The effects of phorbol ester, CCh, and CCK were inhibited by as much as 75% by the PKC inhibitors GF 109203X and Ro-32-0432 and after PKC downregulation. In the absence of extracellular Ca2+, PDBu-, CCh-, and CCK-induced cAMP production was inhibited by 
50% in each case. Chelation of intracellular Ca2+ with 1,2-bis(o-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA/AM) inhibited CCh- and CCK-stimulated cAMP generation by 50% but did not inhibit the stimulatory effect of PDBu. Stringent Ca2+ depletion by removal of extracellular Ca2+ and inclusion of BAPTA/AM allowed for increased cAMP production in response to CCh and CCK; PKC inhibitors and PKC downregulation prevented this stimulation. Glucose stimulation also increased islet cAMP production, but PDBu did not potentiate the glucose response. The results suggest that Ca2+ influx, Ca2+ mobilization, and PKC activation play important roles in the modulation of AC activity in pancreatic islets.
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