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Proton‐gated coincidence detection is a common feature of GPCR signaling
Author(s) -
Kapolka Nicholas,
Rowe Jacob,
Taghon Geoffrey,
Morgan William,
O'Shea Corin,
Isom Daniel
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04123
Subject(s) - g protein coupled receptor , biology , receptor , molecular pharmacology , endosome , signal transduction , rhodopsin like receptors , computational biology , microbiology and biotechnology , neuroscience , chemistry , biochemistry , agonist , metabotropic receptor
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 logic gates capable of discerning multiple inputs to transduce cues encoded in complex, context‐dependent signals. Here, we show that many GPCRs are switch‐like Boolean‐gated 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 a new acid sensor, the adenosine A2a receptor (ADORA2A), which can be activated solely by acidic pH. Together, these findings establish a new paradigm for GPCR biology and pharmacology in acidified microenvironments such as endosomes, synapses, tumors, and ischemic vasculature.