Adenylyl cyclase signalling complexes – Pharmacological challenges and opportunities

Abstract

Signalling pathways involving the vital second messanger, cAMP, impact on most significant physiological processes. Unsurprisingly therefore, the activation and regulation of cAMP signalling is tightly controlled within the cell by processes including phosphorylation, the scaffolding of protein signalling complexes and sub-cellular compartmentalisation. This inherent complexity, along with the highly conserved structure of the catalytic sites among the nine membrane-bound adenylyl cyclases, presents significant challenges for efficient inhibition of cAMP signalling. Here, we will describe the biochemistry and cell biology of the family of membrane-bound adenylyl cyclases, their organisation within the cell, and the nature of the cAMP signals that they produce, as a prelude to considering how cAMP signalling might be perturbed. We describe the limitations associated with direct inhibition of adenylyl cyclase activity, and evaluate alternative strategies for more specific targeting of adenylyl cyclase signalling. The inherent complexity in the activation and organisation of adenylyl cyclase activity may actually provide unique opportunities for selectively targeting discrete adenylyl cyclase functions in disease.

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.