Abstract
Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects. A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology. Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability.
Highlights
In cardiomyocytes, the influx of Ca2+ ions through voltage-dependent L-type Ca2+ channels (LTCC) plays an essential role in cardiac excitability and in coupling excitation to contraction of these cells
It revealed for instance an increase in β-adrenergic receptor (β-AR) dependent inotropic response and cAMP accumulation in isolated ventricular cardiomyocytes (Melsom et al, 2014), confirming the dual coupling of β2-AR to both Gαi and Gαs (Xiao, 2001) in the cardiac tissue
Efetova et al pioneered the use of bPAC to distinguish between the functions of alternative cAMP effectors in the in vivo regulation of a Drosophila melanogaster physiological process (Efetova et al, 2013) while Von Zastrow’s group recently used the bPAC fused to different targeting sequences to assess the role of cAMP compartmentation in G protein-coupled receptors (GPCRs) signaling (Tsvetanova and von Zastrow, 2014)
Summary
The influx of Ca2+ ions through voltage-dependent L-type Ca2+ channels (LTCC) plays an essential role in cardiac excitability and in coupling excitation to contraction of these cells. The depolarizing current through LTCC (ICa) contributes to the plateau phase of the cardiac action potential as well as to pacemaker activity in nodal cells (Shaw and Colecraft, 2013). This influx of Ca2+ triggers the release of intracellular stores of Ca2+ from the sarcoplasmic reticulum via the Ryanodine receptor (RyR), which results in activation of myofilaments contraction. CAMP is produced by adenylyl cyclases (AC) Extracellular stimuli such as neurotransmitters, hormones, chemokines, lipid mediators, and drugs, can modulate AC activity to increase or decrease cAMP production by binding to a large number of transmembrane G protein-coupled receptors (GPCRs). Once cAMP is produced it activates a set of diverse proteins, including
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