Inhibition of adenylate cyclase of rat hepatic membranes by glycosaminoglycans.
Glycosaminoglycans are long non-branched polysaccharides composed of repeating disaccharide units. In a previous in vitro study we have shown that such molecules are able to modulate substrate phosphorylation catalyzed by cAMP-dependent protein kinase. Here, we investigate the impact of glycosaminoglycans, such as heparan sulfate, dermatan sulfate, chondroitin 4- and 6-sulfate, keratan sulfate and hyaluronic acid upon adenylate cyclase, which directly regulates cAMP-dependent protein kinase activity via cAMP synthesis. In rat liver plasma membrane preparation we have determined forskolin- and guanosine-5'-beta, gamma-imidotriphosphate-induced cAMP formation catalyzed by adenylate cyclase in the presence of increasing concentrations of glycosaminoglycans. The results indicate that glycosaminoglycans strongly influence enzymic conversion of ATP into cAMP. The highest reduction of adenylate cyclase activity is observed in the presence of dermatan sulfate and heparan sulfate. Moreover, the inhibitory effect of these two glycosaminoglycans is higher when guanosine-5'-beta, gamma-imidotriphosphate, instead of forskolin, is used as stimulator of adenylate cyclase. Further characterization of enzyme inhibition mediated by dermatan sulfate shows that this molecule exerts an inhibitory effect of mixed type.
Dittmann
J
J
Institut für Physiologische Chemie, Tierärztliche Hochschule Hannover, Germany. Jdittman@biochemie.tiho-hannover.de
Keller
C
C
Harisch
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002384:Catalysis; D002417:Cattle; D002462:Cell Membrane / Q000201:enzymology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D006025:Glycosaminoglycans; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP