Adenylate cyclase-centred microdomains.

Abstract

Recent advances in the AC (adenylate cyclase)/cAMP field reveal overarching roles for the ACs. Whereas few processes are unaffected by cAMP in eukaryotes, ranging from the rapid modulation of ion channel kinetics to the slowest developmental effects, the large number of cellular processes modulated by only three intermediaries, i.e. PKA (protein kinase A), Epacs (exchange proteins directly activated by cAMP) and CNG (cyclic nucleotide-gated) channels, poses the question of how selectivity and fine control is achieved by cAMP. One answer rests on the number of differently regulated and distinctly expressed AC species. Specific ACs are implicated in processes such as insulin secretion, immunological responses, sino-atrial node pulsatility and memory formation, and specific ACs are linked with particular diseased conditions or predispositions, such as cystic fibrosis, Type2 diabetes and dysrhythmias. However, much of the selectivity and control exerted by cAMP lies in the sophisticated properties of individual ACs, in terms of their coincident responsiveness, dynamic protein scaffolding and organization of cellular microassemblies. The ACs appear to be the centre of highly organized microdomains, where both cAMP and Ca2+, the other major influence on ACs, change in patterns quite discrete from the broad cellular milieu. How these microdomains are organized is beginning to become clear, so that ACs may now be viewed as fundamental signalling centres, whose properties exceed their production of cAMP. In the present review, we summarize how ACs are multiply regulated and the steps that are put in place to ensure discrimination in their signalling. This includes scaffolding of targets and modulators by the ACs and assembling of signalling nexuses in discrete cellular domains. We also stress how these assemblies are cell-specific, context-specific and dynamic, and may be best addressed by targeted biosensors. These perspectives on the organization of ACs uncover new strategies for intervention in systems mediated by cAMP, which promise far more informed specificity than traditional approaches.