Gsα stimulation of mammalian adenylate cyclases regulated by their hexahelical membrane anchors

In 1989, the first sequencing of a mammalian adenylate cyclase (AC) identified two related, complementary catalytic domains (C1 and C2) and two dissimilar hexahelical membrane anchors (TM1 and TM2). The voluminous membrane anchoring domains have been proposed to possess unconfirmed properties of an ion channel or a transporter. These membrane-delimited ACs (mACs) serve as cellular effector proteins for numerous hormones signaling via G protein-coupled receptors (GPCRs). Nine distinct AC isoforms exist, each with TM1 and TM2 domains and complementary C1/C2 domains forming the catalytic center at their interface. Previous work determined that Gsα stimulates catalytic activity independently of the membrane anchors, i.e. the membrane anchors appear dispensable for both catalysis and regulation. Obviously, there is a need to better understand the physiological functions of the two membrane domains aside from anchoring as they are isoform-specifically conserved in evolution for more than half a billion years. To this note, A. Seth and J. E. Schultz from the school of pharmacy together with M. Finkbeiner and J. Grischin from at the Max-Planck-Institute for Developmental Biology at Tübingen, Germany, successfully identified additional important properties of the membrane domains of mACs using a series of bioinformatic, molecular and functional studies. They demonstrated that the membrane anchors of mACs are orphan receptors, and, thus, established a new level of AC regulation. The work was recently published in the Journal of Cellular Signalling.

The research team proposed a new three-state model of mAC regulation that fully encompasses all biochemical, structural and pharmacological data known about the mACs to date. They proposed the existence of an allosteric linkage in mACs, in which the membrane anchors, as receptors, transduce extracellular signals across the cell membrane to the cytosolic catalytic dimer. This way, each mAC isoform can be addressed individually by an extracellular ligand and primed for a physiologically measured GPCR/Gsα response. The proposed model by the German scientists may rationalize why multiple Gsα-stimulated mAC isoforms are often expressed in a single cell. The findings considerably expand our view of signaling via mACs and GPCR’s which are a preferred target of a considerably fraction of current drugs.

Through this carefully designed study, the authors added a novel general regulatory input to mAC activation which will serve as a foundation for future studies such identification of cognate ligands.