Compartmentation of G Protein-Coupled Signaling Pathways in Cardiac Myocytes

Abstract

There is a large body of functional data that supports the existence of subcellular compartmentation of the components of cyclic AMP action in the heart. Data from isolated perfused hearts and from purified ventricular myocytes imply a fixed and hormone-specific spatial relationship amongst components of cyclic AMP synthesis, response, and degradation. Available data demonstrate that within a cardiac myocyte, not all cyclic AMP gains access to all cyclic AMP-dependent protein kinase (PKA), that not all PKA interacts with all possible cellular substrates of PKA, and that only a subset of the myocyte's phosphodiesterases (PDEs) may degrade cyclic AMP after a given synthetic stimulus. Molecular mechanisms contributing to compartmentation are being discovered: localization of receptors, G proteins, and adenylyl cyclases in caveolar versus noncaveolar regions of the sarcolemma; localization of PKA by A-kinase anchoring proteins; localization of PKA substrates, PDE isoforms, and phosphoprotein phosphatases in discrete subcellular regions; and differential regulation of multiple isoforms of adenylyl cyclase, phosphoprotein phosphatase, and PDE in distinct subcellular compartments.

Effects of forskolin on inotropic performance and phospholamban phosphorylation in exercise-trained hypertensive myocardium

“…However, differences in the cellular compartmentation of the cAMP system are also an important consideration. Although both isoproterenol and forskolin are known to increase LV inotropic and lusitropic function via increasing cAMP (8,18,22), it is hypothesized that cellular compartmentation allows for a more profuse increase in [Ca 2ϩ ] i and contractility with isoproterenol (18,23,48). Patchclamp experiments in LV cardiomyocytes show L-type Ca 2ϩ current is more localized to the ␤-AR with isoproterenol, whereas L-type Ca 2ϩ current is more widely dispersed throughout the entire sarcolemma with forskolin (25).…”

“…Forskolin activates adenylate cyclase by binding to the cytosolic domain of the membrane-bound enzyme and leads to cAMP generation in a reversible manner, irrespective of cell surface receptors (44). This is of particular interest because, although both direct ␤-AR agonism with isoproterenol and downstream signaling with forskolin result in a dosedependent increase in intracellular cAMP, differences in cellular compartmentation of these systems allow for a more prolific rise in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and inotropy with isoproterenol (18,23,25,45,48). Moreover, since PKA can phosphorylate and uncouple ␤-AR signaling, we also examined whether concurrent forskolin and isoproterenol infusion would induce a differential inotropic response in the hypertensive sedentary and trained myocardium.…”

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

“…For instance, the ␤-adrenergic agonist isoprenaline (ISO), 1 prostaglandin E 1 (PGE 1 ), and glucagon-like peptide 1 (GLP-1) elevate intracardiac cAMP levels with different effects on contractility; ISO augments the force of contraction, PGE 1 does not, and GLP-1 exerts a negative inotropic effect (4,5). In order to explain these results, subcellular compartmentation of cAMP was proposed more than 20 years ago (6).…”

Rôle des phosphodiestérases des nucléotides cycliques de types 3 et 4 dans le couplage excitation-contraction et les arythmies cardiaques

“…En plus des récepteurs -AR, les myocytes cardiaques expriment d'autres récepteurs couplés à G s qui, bien qu'activant la même voie de signalisation, exercent des effets différents sur le coeur [9]. Une Le schéma illustre les éléments fondamentaux responsables des mouvements calciques et de la contraction à l'intérieur d'un myocyte cardiaque.…”