Abstract
3′,5′-cyclic adenosine monophosphate (cAMP) signalling plays a major role in the cardiac myocyte response to extracellular stimulation by hormones and neurotransmitters. In recent years, evidence has accumulated demonstrating that the cAMP response to different extracellular agonists is not uniform: depending on the stimulus, cAMP signals of different amplitudes and kinetics are generated in different subcellular compartments, eliciting defined physiological effects. In this review, we focus on how real-time imaging using fluorescence resonance energy transfer (FRET)-based reporters has provided mechanistic insight into the compartmentalisation of the cAMP signalling pathway and allowed for the precise definition of the regulation and function of subcellular cAMP nanodomains.
Highlights
Cyclic nucleotides, such as 3,5 -adenosine monophosphate, are small molecules used by cells to propagate extracellular information inside the cell and are referred to as second messengers. cAMP is generated by intracellular adenylyl cyclases in response to a first, extracellular message that activates a transmembrane G-protein coupled receptor (GPCR)
Increases in cAMP can activate different families of cAMP-binding proteins. These include cyclic nucleotide-gated ion channels (CNGC) [2], exchange proteins directly activated by cAMP (Epacs) [3], Popeye domain-containing (POPDC) proteins [4], and protein kinase A (PKA) [5]
The use of fluorescence resonance energy transfer (FRET)-based cAMP and PKA activity sensors has greatly enhanced our understanding of spatial organisation in the cAMP signalling cascade, as well as the mechanisms that generate a uniquely patterned cAMP response through cardiomyocytes as they react to defined stimuli
Summary
Cyclic nucleotides, such as 3 ,5 -adenosine monophosphate (cAMP), are small molecules used by cells to propagate extracellular information inside the cell and are referred to as second messengers. cAMP is generated by intracellular adenylyl cyclases in response to a first, extracellular message that activates a transmembrane G-protein coupled receptor (GPCR). Not all extracellular stimuli that activate cAMP signalling in the heart increase PKA activity uniformly and to a similar degree throughout the cell This was first hypothesised on the basis of observations in biochemical fractions of cardiomyocytes, stimulated with either prostaglandins or β-adrenergic receptor agonists [6]. Clean isolation of cardiomyocyte organelles, to map the heterogenic distribution of cAMP across the cell on a micrometre scale, presents a considerable challenge Another experimental difficulty is the small molecular size of cAMP itself: cAMP occupies not more than 1.12 nm in a crystal structure in complex with PDE4D (PDB 2PW3) [7], which is more than six times smaller than the Gsα subunit of a heterotrimeric G protein (PDB 1AZT) [8]. AEcCc5e0pftoorr.cEACM50Pfoisr cinAdMicPatiesdinfodricaaltlecdAfMorPadllectAecMtioPndseytestcetmions, sayssrteepmosr,taesdrienptohretelditeirnatthuereli[t1e0ra–t1u3r]e. [10,11,12,13]
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