Proton-gated coincidence detection is a common feature of GPCR signaling

Nicholas J. Kapolka, Jacob B. Rowe, Geoffrey J. Taghon, William M. Morgan, Corin R. O’Shea, Daniel G. Isom

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The evolutionary expansion of G protein-coupled receptors (GPCRs) has produced a rich diversity of transmembrane sensors for many physical and chemical signals. In humans alone, over 800 GPCRs detect stimuli such as light, hormones, and metabolites to guide cellular decision-making primarily using intracellular G protein signaling networks. This diversity is further enriched by GPCRs that function as molecular sensors capable of discerning multiple inputs to transduce cues encoded in complex, context-dependent signals. Here, we show that many GPCRs are coincidence detectors that couple proton (H+) binding to GPCR signaling. Using a panel of 28 receptors covering 280 individual GPCR-Gα coupling combinations, we show that H+ gating both positively and negatively modulates GPCR signaling. Notably, these observations extend to all modes of GPCR pharmacology including ligand efficacy, potency, and cooperativity. Additionally, we show that GPCR antagonism and constitutive activity are regulated by H+ gating and report the discovery of an acid sensor, the adenosine A2a receptor, which can be activated solely by acidic pH. Together, these findings establish a paradigm for GPCR signaling, biology, and pharmacology applicable to acidified microenvironments such as endosomes, synapses, tumors, and ischemic vasculature.

Original languageEnglish (US)
Article numberPNAS 2021 Vol. 118 No. 28 e2100171118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number28
StatePublished - Jul 13 2021
Externally publishedYes


  • Acidosis
  • Boolean
  • Coincidence detection
  • GPCR
  • Proton gating

ASJC Scopus subject areas

  • General


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