Distinct glycerophospholipids potentiate Gsα-activated adenylyl cyclase activity

Abstract

Nine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical 29 membrane domains which are isoform-specifically conserved. Previously we proposed that these 30 membrane domains are orphan receptors (10.7554/eLife.13098; 10.1016/j.cellsig.2020.109538). 31 Lipids extracted from fetal bovine serum at pH 1 inhibited several mAC activities. Guided by a 32 lipidomic analysis we tested glycerophospholipids as potential ligands. Contrary to expectations 33 we surprisingly discovered that 1-stearoyl-2-docosahexaenoyl-phosphatidic acid (SDPA) 34 potentiated Gsα-activated activity of human AC isoform 3 seven-fold. The specificity of fatty 35 acyl esters at glycerol positions 1 and 2 was rather stringent.