REGULATION OF ADENYLYL-CYCLASE BY PROTEIN-KINASE-A

The changing relationship between stimuli and responses after prolonge d receptor stimulation is a general feature of hormonal signaling syst ems, termed desensitization. This phenomenon has been best exemplified in the covalent modification of the G protein-linked catecholamine re ceptors. However, other components within this signaling pathway can b e involved in desensitization. Here we present evidence that desensiti zation occurs at the level of the effector enzyme itself through phosp horylation. Type V adenylyl cyclase (AC) is the major isoform expresse d in the heart. Using purified enzymes, we demonstrate that protein ki nase A (PKA) directly phosphorylates and thereby inhibits type V AC ca talytic activity, This inhibition was negated in the presence of PKA i nhibitor. Analysis of enzyme kinetics revealed that this inhibition wa s due to a decrease in the catalytic rate, not to a decrease in the af finity for the substrate ATP. Our results indicate that AC catalytic a ctivity can be regulated through PKA-mediated phosphorylation, suggest ing another mechanism of desensitization for receptor pathways which s ignal via increases in intracellular cAMP.