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

Abstract

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.

Keywords: Ca(2+); G-protein-coupled receptor; IP(3) receptor; Sigma-1 receptor; bradykinin; choline; intracellular messenger; neurotransmitter; phospholipase C; phospholipase D.