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

Authors

Eugen Brailoiu, Temple University
Sumita Chakraborty, Cambridge
G. Cristina Brailoiu, Thomas Jefferson UniversityFollow
Pingwei Zhao, Tennessee Temple University
Jeffrey L. Barr, Temple University
Marc A. Ilies, Temple University
Ellen M. Unterwald, Temple University
Mary E. Abood, Temple University
Colin W. Taylor, Cambridge

Document Type

Article

Publication Date

1-8-2019

Comments

This article has been peer reviewed. It is the author’s final published version in Cell Reports, Volume 26, Issue 2, January 2019, Pages 330-337.e4.

The published version is available at https://doi.org/10.1016/j.celrep.2018.12.051. Copyright © Brailoiu et al.

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. © 2018 The Authors

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 Ca²⁺ release through IP₃ receptors. © 2018 The Authors

Recommended Citation

Brailoiu, Eugen; Chakraborty, Sumita; Brailoiu, G. Cristina; Zhao, Pingwei; Barr, Jeffrey L.; Ilies, Marc A.; Unterwald, Ellen M.; Abood, Mary E.; and Taylor, Colin W., "Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors" (2019). College of Pharmacy Faculty Papers. Paper 36.
https://jdc.jefferson.edu/pharmacyfp/36

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30625315

Language

English