Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP ₃ -Evoked Ca ²⁺ Signals through Sigma-1 Receptors

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 (IP ₃ Rs) that release Ca ²⁺ 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 Ca ²⁺ signals evoked by IP ₃ Rs, and it is deactivated by metabolism. Receptors, by stimulating PLC and PLD, deliver two signals to IP ₃ Rs: IP ₃ activates IP ₃ Rs, 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 Ca ²⁺ signals. We conclude that choline is an endogenous agonist of Sig-1Rs linking extracellular stimuli, and perhaps synaptic activity, to Ca ²⁺ signals.