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 3Rs) 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 3Rs, and it is deactivated by metabolism. Receptors, by stimulating PLC and PLD, deliver two signals to IP 3Rs: IP 3 activates IP 3Rs, 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.
Choline, but not its metabolites, binds to Sigma-1 receptors
Choline potentiates IP 3-evoked Ca 2+ release by activating Sigma-1 receptors
Bradykinin stimulates Ca 2+ release by stimulating formation of IP 3 and choline
Choline uptake by a specific transporter potentiates IP 3-evoked Ca 2+ release
Sigma-1 receptors respond to diverse stimuli and regulate many signaling proteins. Brailoiu et al. show that choline is an endogenous agonist of Sigma-1 receptors. Choline links receptors and cholinergic synaptic activity, through Sigma-1 receptors, to enhanced Ca 2+ release through IP 3 receptors.