INHIBITION OF ADENYLATE-CYCLASE OF RAT HEPATIC MEMBRANES BY GLYCOSAMINOGLYCANS

Glycosaminoglycans are long non-branched polysaccharides composed of r epeating disaccharide units. In a previous in vitro study we have show n that such molecules are able to modulate substrate phosphorylation c atalyzed by cAMP-dependent protein kinase. Here, we investigate the im pact of glycosaminoglycans, such as heparan sulfate, dermatan sulfate, chondroitin 4- and B-sulfate, keratan sulfate and hyaluronic acid upo n adenylate cyclase, which directly regulates cAMP-dependent protein k inase activity via cAMP synthesis. In rat liver plasma membrane prepar ation we have determined forskolin- and guanosine-5'-beta,gamma-imidot riphosphate-induced cAMP formation catalyzed by adenylate cyclase in t he presence of increasing concentrations of glycosaminoglycans. The re sults indicate that glycosaminoglycans strongly influence enzymic conv ersion of ATP into cAMP. The highest reduction of adenylate cyclase ac tivity is observed in the presence of dermatan sulfate and heparan sul fate. Moreover, the inhibitory effect of these two glycosaminoglycans is higher when guanosine-5'-beta,gamma-imidotriphosphate, instead of f orskolin, is used as stimulator of adenylate cyclase. Further characte rization of enzyme inhibition mediated by dermatan sulfate shows that this molecule exerts an inhibitory effect of mixed type.