DSSS - The Membrane Domains of Adenylyl Cyclases Define a New Level of Regulation

3’,5’-Adenosine monophosphate (cyclic AMP) is an intracellular second messenger which regulates vital processes in all cells, tissues and organs in vertebrates. cAMP is synthesized by 9 membrane-delimited class III adenylyl cyclase isoforms (ACs) of identical domain composition. They are pseudoheterodimers comprising two hexahelical membrane and two complementing catalytic domains. The catalytic domains are conserved for >2 billion years. All other domains are conserved in an isoform-specific manner for at least 500 million yrs. We show that the membrane domains of mammalian ACs are receptors for aliphatic fatty acid ligands. Receptor activation directly affects the known indirect stimulation of ACs via G-protein-coupled receptors and the intracellular Gsα protein -- so far considered the exclusive regulatory mechanism. Thus, we discovered a new level of regulation of the cAMP biosynthesis combining two signaling modalities in one protein: direct tonic signaling via lipid ligands and indirect phasic signaling via GPCR-Gsα axis. The direct signaling is evolutionarily old, as demonstrated by lipid regulation of a mycobacterial AC.
The data may open the universal cAMP signaling system to a completely new and underexplored class of receptor ligands: lipids.