A signal transduction blind spot: the function of adenylyl cyclase transmembrane domains

Signal transduction of external primary signals into intracellular elevations of the second messenger cyclic AMP is an ancient and universal regulatory mechanism in biology. In mammals, 9 of the 10 adenylyl cyclases (ACs) share a common topology that includes a large transmembrane (TM) domain assembled from two clusters of six helices. This domain accounts for similar to 35% of the coding sequence but, remarkably, its function is still an open question. In this viewpoint, we consider how the first primary AC sequences spurred ideas for the purpose of AC TM domains, including voltage-sensing and transporter functions. In the original conceptions of second messenger signalling, ACs were put forward as potential receptors, and we discuss emerging evidence in support of this function. We also consider growing evidence that cyclase TM helical bundles help to organise multiprotein signalling complexes by engaging in interactions with other membrane-embedded proteins. Cyclase TM regions are more diverse between isoforms than the catalytic domain-we conclude by considering how this might be exploited in therapeutic strategies targeting specific cyclase isoforms.