Evolving perspectives on lipid mediated cell-to-cell communication: The adenylyl cyclase signaling system

Decades after the discovery of the second messenger cyclic AMP, the regulation of multi-domain adenylyl cyclases remains poorly understood. Mammals express nine membrane-bound isoforms which share an identical domain architecture. These mACs act as downstream effectors of G protein-coupled receptors (GPCRs) and are activated by the release of Gα subunits from heterotrimeric G proteins. Bioinformatic analyses reveal isoform-specific conservation of all mAC domains across more than 500 million years of evolution. The membrane domains function as inhibitory or activating receptors, with unsaturated fatty acids as their ligands. Notable, a similar regulatory mechanism was uncovered in a mycobacterial mAC. This perspective contextualizes previous findings and explores emerging questions regarding signaling via lipid ligands in the cAMP generating system. Due to their low water solubility, fatty acid ligands are likely produced locally at cell-cell contact sites, establishing a semi-stable level of tonic signaling. This suggests the existence of an as-yet unknown link between intercellular lipid signaling and the GPCR-cAMP pathways. Since ligand dissociation appears unlikely, lipid-receptor binding may mark receptors for internalization, recycling, and, possibly, degradation. The potential repertoire of mAC regulation is considered in view of the existence of additional highly conserved domains including those at the N- and C-termini.