Catecholamines also induce PKA-mediated phosphorylation of phospholamban (PLB), a negative regulator of the sarcoplasmic reticulum Ca 2+ ATPase (SERCA), resulting in increased Ca 2+ re-uptake in the sarcoplasmic reticulum and myofilament relaxation (lusitropic effect) ( Bers, 2008). In addition, β-adrenoceptors stimulation leads to PKA-mediated phosphorylation of troponin I (TnI), accelerating troponin C-Ca 2+ off-rate and allowing faster force development and shortening during systole and faster force relaxation and re-lengthening during diastole ( Bers, 2008). In cardiac myocytes, cAMP generated in response to catecholamine-mediated, β-adrenoceptors stimulation modulates excitation contraction coupling by activating PKA and the subsequent phosphorylation of the L-type Ca 2+ channel (LTCC) and the ryanodine receptor (RyR), thus increasing the amount of Ca 2+ available for contraction (positive inotropic effect). Even at the single cell level, the cAMP/PKA signalling system is involved in a multitude of diverse functions. cAMP activates a limited number of intracellular targets including protein kinase A (PKA), the exchange proteins activated by cAMP and cyclic nucleotide-gated channels, and by doing so it controls a bewildering number of cellular functions, ranging from cell growth and differentiation to cell movement and migration, from learning and memory formation to control of hormone secretion, metabolism and gene transcription ( Francis and Corbin, 1994). Most of the details of the molecular organization and regulation of individual cAMP signalling compartments are still to be elucidated but future research should provide the knowledge necessary to develop and test new therapeutic strategies that, by acting on a limited subset of downstream targets, would improve efficacy and minimize off-target effects.ģ′-5′-cyclic adenosine monophosphate (cAMP) is a small and diffusible intracellular second messenger generated in response to binding of a number of hormones and neurotransmitters to G-protein-coupled receptors (GPCRs). A growing body of evidence points to the spatial organization of the components of the cAMP signalling pathway in distinct, spatially segregated signalling domains as the key feature underpinning specificity of response and data is emerging, indicating that alteration of spatial control of the cAMP signal cascade associates with heart pathology. In the heart, cAMP mediates the catecholaminergic control on heart rate and contractility but, at the same time, it is responsible for the functional response to a wide variety of other hormones and neurotransmitters, raising the question of how the myocyte can decode the cAMP signal and generate the appropriate functional output to each individual extracellular stimulus. 3′-5′-cyclic adenosine monophosphate (cAMP) is a pleiotropic intracellular second messenger generated in response to activation of G s protein-coupled receptors.
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