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The changing relationship between stimuli and responses after
prolonged receptor stimulation is a general feature of hormonal
signaling systems, termed desensitization. This phenomenon has been
best exemplified in the covalent modification of the G protein-linked
catecholamine receptors. However, other components within this
signaling pathway can be involved in desensitization. Here we present
evidence that desensitization occurs at the level of the effector
enzyme itself through phosphorylation. Type V adenylyl cyclase (AC) is
the major isoform expressed in the heart. Using purified enzymes, we
demonstrate that protein kinase A (PKA) directly phosphorylates and
thereby inhibits type V AC catalytic activity. This inhibition was
negated in the presence of PKA inhibitor. Analysis of enzyme kinetics
revealed that this inhibition was due to a decrease in the catalytic
rate, not to a decrease in the affinity for the substrate ATP. Our
results indicate that AC catalytic activity can be regulated through
PKA-mediated phosphorylation, suggesting another mechanism of
desensitization for receptor pathways which signal via increases in
intracellular cAMP.
Volume 270,
Number 21,
Issue of May 26, pp. 12481-12484, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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