Harnessing ion-binding sites for GPCR pharmacology

Barbara Zarzycka, Saheem A. Zaidi, Bryan L. Roth, Vsevolod Katritch*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Endogenous ions play important roles in the function and pharmacology of G-protein coupled receptors (GPCRs). Historically the evidence for ionic modulation ofGPCRfunction dates to 1973 with studies of opioid receptors, where it was demonstrated that physiologic concentrations of sodium allosterically attenuated agonist binding. This Na+-selective effect was distinct from effects of other monovalent and divalent cations, with the latter usually counteracting sodium’s negative allosteric modulation of binding. Since then, numerous studies documenting the effects of mono- and divalent ions on GPCR function have been published. While ions can act selectively and nonselectively at many sites in different receptors, the discovery of the conserved sodium ion site in class A GPCR structures in 2012 revealed the unique nature of Na+ site, which has emerged as a near-universal site for allosteric modulation of class A GPCR structure and function. In this review, we synthesize and highlight recent advances in the functional, biophysical, and structural characterization of ions bound to GPCRs. Taken together, these findings provide a molecular understanding of the unique roles of Na+ and other ions as GPCR allosteric modulators. Wewill also discuss how this knowledge can be applied to the redesign of receptors and ligand probes for desired functional and pharmacological profiles.

Original languageEnglish
Pages (from-to)571-595
Number of pages25
JournalPharmacological Reviews
Issue number4
Publication statusPublished - 1 Oct 2019
Externally publishedYes


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