Associate editor: E. KlussmannAdenylyl cyclase signalling complexes – Pharmacological challenges and opportunities
Introduction
The concept that hormones or other cellular regulators act from outside the cell to generate an internal second messenger arose with cAMP. The nucleotide is involved in regulating numerous processes, that can range from fast to slow, or from widespread to highly specialised. It occupies a paradigmatic place in cellular signalling in that, rightly or wrongly, the issues surrounding cAMP signalling became paradigms for how second messenger signalling was to be viewed in general. Thus, the principles established in cAMP signalling either translate directly to other systems or at least they have been assessed in other systems. For example, the cAMP field established phosphorylation and kinases as one of the major covalent devices for regulating cellular activity. Phosphorylation cascades, with their cycles of intertwined feedbacks and feed forwards of phosphorylation and dephosphorylation, are now accepted as the central motif of cellular signalling. Of course, mechanisms for terminating signals are just as important in shaping the nature and range of signals. The scaffolding of numerous signalling proteins is key to the actions and regulation of growth factors and both this concept and its application were readily established for cAMP signalling. In this way, recognition of the organisation inherent in cAMP signalling was a reciprocal benefit from exporting the notion of phosphorylation cascades from the cAMP to growth factor fields. Localism – a consequence of organisation in signalling – may have been proposed by the development of calcium dyes and the elegant organisation of cardiomyocyte calcium signalling, but it is today a directly demonstrable cornerstone feature of cAMP signalling.
Notwithstanding the sixty-year study of cAMP, and the range of processes that cAMP regulates, or perhaps because of the complexity now surrounding cAMP signalling, strategies for interrupting cAMP signalling need to go far beyond the simple level of inhibition of the enzyme that produces the signal, adenylyl cyclase (AC). In this regard cAMP may yet again be pointing the way forward to creative strategies for interfering with general signalling processes. In this review we will address the family of ACs, in terms of their physiological roles, their biochemical and cell biological properties, their organisation and association within the cell, and the nature of cAMP signals. We will assess strategies for interfering with cAMP signalling at these various points in an effort to direct us towards the most fruitful way of addressing the roles of this central second messenger.
Section snippets
Adenylyl cyclases exert complex physiological effects
Cyclic AMP can impact on most significant physiological processes, from regulatory events to metabolism to growth and differentiation. For instance, cAMP has dramatic effects on the regulation of cardiac contractility by the sympathetic nervous system by affecting ion channels and pumps (reviewed in Boularan and Gales, 2015, Efendiev and Dessauer, 2011); it is centrally involved in the control of glycogenolysis and lipolysis (reviewed in Ravnskjaer, Madiraju, & Montminy, 2016), as well as in
Inhibit catalytic activity
ACs catalyse the conversion of a Mg2 +.ATP complex to cAMP, by creating a cyclic phosphodiester bond based on the α-phosphate group of ATP and releasing pyrophosphate (PPi) (Fig. 3). The release of PPi both yields energy for the reaction and it's dissociation is ultimately the rate-limiting step in cAMP production (Dessauer, 2002). As the determinants of nucleotide binding and catalysis are shared between the two catalytic domains (termed C1 and C2), any change in this relative orientation will
Conclusions
The ubiquity of cAMP involvement in regulating numerous physiological processes provides a key opportunity to modulate these events. We have outlined the themes that have evolved to constrain and finetune the actions of cAMP, from the activation of ACs to their selective associations and placement within the cell. The range of elaborate devices that describe cAMP signalling in particular contexts provide potentially unique assemblies that may be amenable to specific perturbation, should
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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These authors contributed equally to this work.