Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors.

Eugen Brailoiu, Sumita Chakraborty, G Cristina Brailoiu, Pingwei Zhao, Jeffrey L Barr, Marc A Ilies, Ellen M Unterwald, Mary E Abood, Colin W Taylor

OAI: oai:www.repository.cam.ac.uk:1810/288470 • DOI: 10.17863/CAM.35757

Sigma-1 receptors (Sig-1Rs) are integral ER membrane proteins. They bind diverse ligands, including psychoactive drugs, and regulate many signaling proteins, including the inositol 1,4,5-trisphosphate receptors (IP3Rs) that release Ca2+ from the ER. The endogenous ligands of Sig-1Rs are unknown. Phospholipase D (PLD) cleaves phosphatidylcholine to choline and phosphatidic acid (PA), with PA assumed to mediate all downstream signaling. We show that choline is also an intracellular messenger. Choline binds to Sig-1Rs, it mimics other Sig-1R agonists by potentiating Ca2+ signals evoked by IP3Rs, and it is deactivated by metabolism. Receptors, by stimulating PLC and PLD, deliver two signals to IP3Rs: IP3 activates IP3Rs, and choline potentiates their activity through Sig-1Rs. Choline is also produced at synapses by degradation of acetylcholine. Choline uptake by transporters activates Sig-1Rs and potentiates Ca2+ signals. We conclude that choline is an endogenous agonist of Sig-1Rs linking extracellular stimuli, and perhaps synaptic activity, to Ca2+ signals.

Ca(2+) G-protein-coupled receptor IP(3) receptor Sigma-1 receptor Bradykinin Choline intracellular messenger neurotransmitter phospholipase C Phospholipase D Animals Calcium Signaling Cell Line Choline Humans Inositol 1 4 5-Trisphosphate Receptors MCF-7 Cells Mice Phospholipase D Receptors sigma