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

View ORCID ProfileNicholas J. Kapolka, View ORCID ProfileJacob B. Rowe, View ORCID ProfileGeoffrey J. Taghon, View ORCID ProfileWilliam M. Morgan, Corin R. O’Shea, View ORCID ProfileDaniel G. Isom
doi: https://doi.org/10.1101/2021.01.08.425945
Nicholas J. Kapolka
aDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136
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Jacob B. Rowe
aDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136
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Geoffrey J. Taghon
aDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136
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William M. Morgan
aDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136
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Corin R. O’Shea
aDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136
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Daniel G. Isom
aDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136
bUniversity of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136
cUniversity of Miami Institute for Data Science and Computing, Miami, FL 33146
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  • For correspondence: disom@miami.edu
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Abstract

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 link 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 and controls 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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 09, 2021.
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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
bioRxiv 2021.01.08.425945; doi: https://doi.org/10.1101/2021.01.08.425945
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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
bioRxiv 2021.01.08.425945; doi: https://doi.org/10.1101/2021.01.08.425945

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