Abstract
Nine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical membrane domains which are isoform-specifically conserved. Previously we proposed that these membrane domains are orphan receptors (10.7554/eLife.13098; 10.1016/j.cellsig.2020.109538). The identity of the ligands is unknown. Lipids extracted from fetal bovine serum at pH 1 inhibited mAC activities. Guided by a lipidomic analysis we tested glycerophospholipids as ligands. Contrary to the effect of the lipid extract we surprisingly discovered that 1-stearoyl-2-docosahexaenoyl-phosphatidic acid (SDPA) potentiated Gsα-activated activity of human AC isoform 3 seven-fold. The specificity of fatty acyl esters at position 1 and 2 was rather stringent. 1-Stearoyl-2-docosahexaenoyl-phosphatidylserine and 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine significantly potentiated several Gsα-activated mAC isoforms to different extents. SDPA does not interact with forskolin activation of AC isoform 3. SDPA enhanced Gsα-activated AC activities in membranes from mouse brain cortex. The action of SDPA was reversible. SDPA did not affect isoproterenol-stimulated cAMP generation in HEK293 cells indicating a role as an intracellular effector. In summary, we discovered a new dimension of intracellular AC regulation by chemically characterized glycerophospholipids.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations used
- mAC
- membrane-delimited adenylyl cyclase
- GPL
- glycerophospholipid
- SDPA
- 1-stearoyl-2-docosahexaenoyl-phosphatidic acid