Calcium-dependent proteolytic stimulation of adenylate cyclase in platelets from spontaneously hypertensive rats.
Abnormalities of platelet aggregation and cyclic nucleotide metabolism are present in hypertension. We observed a greater increase in the level of cyclic adenosine monophosphate (AMP) after prostaglandin E1 (PGE1) stimulation and a lack of decrease of this cyclic nucleotide by epinephrine in platelets from spontaneously hypertensive rats (SHR) as compared to normotensive rats. The difference in cyclic AMP production between SHR and control rats in response to PGE1 is dependent upon platelet exposure to calcium. Since calcium and cyclic AMP are closely related and are both abnormally regulated in hypertension, we have studied the effect of calcium on adenylate cyclase activity. We show here that two forms of endogenous calcium-dependent proteases (membrane-bound and soluble) stimulate the basal activity and the hormonal responsiveness of adenylate cyclase. The sensitivity of calcium-dependent proteolytic control of adenylate cyclase to very-low concentrations of calcium indicates that the regulation may be physiologically important. Furthermore, calcium exerts a greater influence on platelet adenylate cyclase from SHR than on that from normotensive rats. The adenylate cyclase defect seems to be located in the membrane fraction and may, therefore, result from an increase in the activity of the membrane-bound calcium-protease or may be intrinsic to adenylate cyclase itself. The exact site that is sensitive to proteolysis remains to be established.
D000262:Adenylyl Cyclases / Q000097:blood*; D000527:Alprostadil; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology; D000242:Cyclic AMP / Q000097:blood*; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D010974:Platelet Aggregation; D011458:Prostaglandins E / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood
D002147:Calmodulin; D007976:Leupeptins; D011458:Prostaglandins E; D000242:Cyclic AMP; D010447:Peptide Hydrolases; D012083:Renin; D000262:Adenylyl Cyclases; D000527:Alprostadil; C032854:leupeptin; D002118:Calcium; D004837:Epinephrine