Metal ion and guanine nucleotide regulation of the inhibition of lung adenylate cyclase by adenosine analogs.

Adenosine inhibits guinea-pig lung adenylate cyclase (ATP pyrophosphatelyase (cyclizing), EC 4.6.1.1) through a 'P' type regulatory site. The inhibition is of a non-competitive type. Divalent cations which activate the enzyme (Mg2+ and Mn2+) and also those which inhibit (Ca2+) increase the inhibitory potency of 'P' site analogs at this site. Guanine nucleotides also increase the inhibitory potency at this regulatory site but this does not appear to be directly related to the ability of the guanine nucleotides to activate the enzyme. Other regulators of lung adenylate cyclase, epinephrine and isoproterenol, do not affect the adenosine inhibitory process when examined at physiological concentrations. These studies demonstrate that two types of ligand which regulate the catalytic activity of the lung adenylate cyclase (metal ions and guanine nucleotides) also have a role in regulating the inhibition of the enzyme by adenosine.