© 2001 American Heart Association, Inc.
Editorial |
When Is cAMP Not cAMP?
Effects of Compartmentalization
From the Department of Physiology and Cardiovascular Institute, Loyola University Medical Center, Maywood, Ill.
Correspondence to Donald M. Bers, Department of Physiology, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153. E-mail dbers@lumc.edu
Key Words: glucagon-like peptide-1 • adrenergic signaling • cardiac muscle • cAMP • compartmentalization
Many important cellular processes are controlled via stimulation (or inhibition) of signal transduction systems, among which heptahelical G protein–coupled receptors (GPCRs) figure prominently. A classical example in cardiac myocytes is the ß-adrenergic receptor (ß-AR) cascade (see Figure, panel A), which leads to positive inotropic and lusitropic effects.1 Occupation of the ß-ARs by an agonist activates a GTP binding protein (Gs), such that the 
subunit dissociates and activates adenylyl cyclase (AC), thereby producing cAMP. The increase in cAMP leads to the dissociation of the regulatory and catalytic subunits of protein kinase A (PKA). PKA can be tethered near its substrates by an A-kinase anchoring protein (AKAP). The PKA catalytic subunit phosphorylates several key myocyte proteins involved in excitation-contraction (E-C) coupling, including the L-type Ca2+ channel, phospholamban (PLB), ryanodine receptor (RyR), myosin binding protein C, and troponin I (TnI). These effects produce PKA-dependent increases in Ca2+ current (ICa), sarcoplasmic reticulum (SR) Ca2+ uptake and release, as well as a desensitization of the myofilaments to Ca2+. The net result is the characteristic positive inotropic and lusitropic effects of ß-AR activation in cardiac myocytes.
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The stimulatory effects of GPCR activation can be inhibited at several levels. The receptor can be desensitized by G protein receptor kinases
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