Compartmentalized cAMP signalling and control of cardiac rhythm

Abstract

In the last 30 years, the field of cyclic adenosine 3′,5′-monophosphate (cAMP) signalling has witnessed a transformative development with the realization that cAMP is compartmentalized and that spatial regulation of cAMP is critical for faithful signal propagation and hormonal specificity. This recognition has changed our understanding of cAMP signalling from the canonical model, where a linear pathway connects a plasma membrane receptor to intracellular effectors and their targets, to a model where signal transduction occurs within a complex network of alternative branches and where an individual receptor leads to activation of a limited fraction of the network, enabled by local regulation of independent signalling units, resulting in a specific functional outcome. The cardiac myocyte has served as the cell model for many of the original findings leading to this paradigm. In this review, we cover some of the evidence supporting this new perspective and discuss how this model is providing novel mechanistic insight into cardiac myocyte physiology. With a focus on the regulation of cardiac rhythm, we consider how this model can provide an original framework for the identification of disease mechanisms. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Pacemaker Channels and the Chronotropic Response in Health and Disease

“…Conversely, increased activation of the parasympathetic nervous system causes the release of acetylcholine that binds to G i protein-coupled M 2 muscarinic receptors (CHRM2), thereby inhibiting cAMP synthesis by ACs. The possible mechanisms by which these changes in cytosolic cAMP ultimately accelerate or decelerate the heart 52…”

“…Conversely, increased activation of the parasympathetic nervous system causes the release of acetylcholine that binds to G i protein-coupled M 2 muscarinic receptors ( CHRM2 ), thereby inhibiting cAMP synthesis by ACs. The possible mechanisms by which these changes in cytosolic cAMP ultimately accelerate or decelerate the heart 52 include direct cAMP effects and PKA (protein kinase A)- and CaMKII (Ca 2+ /calmodulin-dependent protein kinase II)-dependent phosphorylation of downstream targets and will be discussed in the ANS Initiates the HR Increasing or Decreasing Effect of the Chronotropic Response section.…”

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

“…These accompany increased protein synthesis and induction of cardiac hypertrophic markers mediated by Ca 2+ -dependent calcineurin activation. Tomek & Zaccolo [ 96 ] describe cellular compartmentation mechanisms in which such diverse cAMP actions might take place. In addition, different sympathetic responses amongst cardiomyocyte types are exemplified by differing electrophysiological properties and responses to noradrenaline of pulmonary vein compared with left atrial cardiomyocytes.…”

Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling

“…PKA is a prominent Ser/Thr kinase that transduces cyclic adenosine monophosphate (cAMP) -mediated signals from many different hormones and neurotransmitters to instruct biological responses ranging from regulation of glucose and lipid metabolism in peripheral tissues, to memory formation and consolidation in the brain [6][7][8][9] . In its inactive state, PKA exists as a holoenzyme composed of a homodimer of two regulatory (R) subunits, each of which in turn holds and inhibits two catalytic subunits.…”