Abstract
3′-5′-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that modulates multiple cellular functions. It is now well established that cAMP can mediate a plethora of functional effects via a complex system of local regulatory mechanisms that result in compartmentalized signalling. The use of fluorescent probes to monitor cAMP in intact, living cells have been instrumental in furthering our appreciation of this ancestral and ubiquitous pathway and unexpected details of the nano-architecture of the cAMP signalling network are starting to emerge. Recent evidence shows that sympathetic control of cardiac contraction and relaxation is achieved via generation of multiple, distinct pools of cAMP that lead to differential phosphorylation of target proteins localized only tens of nanometres apart. The specific local control at these nanodomains is enabled by a distinct signalosome where effectors, targets, and regulators of the cAMP signal are clustered. In this review, we focus on recent advances using targeted fluorescent reporters for cAMP and how they have contributed to our current understanding of nanodomain cAMP signalling in the heart. We briefly discuss how this information can be exploited to design novel therapies and we highlight some of the questions that remain unanswered.
Highlights
The second messenger 30,50-cyclic adenosine monophosphate is involved in multiple physiological functions
In response to a variety of different hormones and other extracellular cues that operate via activation of G protein-coupled receptors (GPCRs), cyclic adenosine monophosphate (cAMP) affects cellular processes that range from modulation of metabolic enzymes to regulation of transcription, from the control of cell survival to cross-talk with multiple other signalling pathways
CAMP activates three ubiquitously expressed intracellular cAMP effector proteins, the cAMP-dependent protein kinase A (PKA), the cyclic nucleotide gated ion channels, and the exchange protein activated by cAMP (Epac) [1]
Summary
30-50-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that modulates multiple cellular functions. It is well established that cAMP can mediate a plethora of functional effects via a complex system of local regulatory mechanisms that result in compartmentalized signalling. Recent evidence shows that sympathetic control of cardiac contraction and relaxation is achieved via generation of multiple, distinct pools of cAMP that lead to differential phosphorylation of target proteins localized only tens of nanometres apart. The specific local control at these nanodomains is enabled by a distinct signalosome where effectors, targets, and regulators of the cAMP signal are clustered. We focus on recent advances using targeted fluorescent reporters for cAMP and how they have contributed to our current understanding of nanodomain cAMP signalling in the heart.
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