© 1997 American Heart Association, Inc.
Articles |
The Adenylyl Cyclases as Integrators of Transmembrane Signal Transduction
the Department of Medicine (Y.I.), Brigham & Women's Hospital, Harvard Medical School, Boston, Mass, and COR Therapeutics Inc (C.J.H.), San Francisco, Calif.
Correspondence to Yoshihiro Ishikawa, MD, PhD, Brigham & Women's Hospital, 221 Longwood Ave, Boston, MA 02115, or Charles J. Homcy, MD, COR Therapeutics Inc, 256 E Grand Ave, South San Francisco, CA 94080.
Key Words: adenylyl cyclase • heart • regulation • transmembrane signaling
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cAMP Generation in the Heart |
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Activation of the sympathetic nerves initiates the most potent stimulus for enhancing cardiac output, both acutely and chronically (Fig 1
). Norepinephrine released into the synaptic cleft at sympathetic nerve terminals binds to ß-adrenergic receptors (ßARs) on the cardiac sarcolemma and activates the stimulatory guanine nucleotide binding protein Gs by promoting the exchange of GDP for GTP. This reaction catalyzes the dissociation of the GTP-bound Gs
subunit from Gß
. GTP-bound Gs then binds to and stimulates adenylyl cyclase. Adenylyl cyclase is a membrane-bound enzyme that catalyzes the conversion of ATP to cAMP.1 cAMP, an intracellular second messenger, activates protein kinase A by dissociating its regulatory subunit from the catalytic subunit.2 The free catalytic subunit thereupon initiates a series of enzymatic reactions leading to a phosphorylation cascade, activating multiple proteins that regulate both the rate and force of cardiac contraction. Phosphorylation of the L-type calcium channel, for example, enhances calcium entry into cardiocytes, leading to increased contractility.3 On phosphorylation of phospholamban, the inhibition exerted by the nonphosphorylated form of phospholamban on the sarcoplasmic reticulum calcium pump is removed, and its rate of calcium uptake is increased, thereby leading to a more rapid decrease of the cytosolic calcium concentration during diastole.4 Dissociation of the troponin C–calcium complex is also enhanced when troponin I is phosphorylated, which leads to an accelerated relaxation rate. These latter events underlie the lusitropic effects of ßAR stimulation.5 Thus, a series of reactions occurs within cardiocytes that is initiated at the level of the cell surface ßAR. This article has been cited by other articles:
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