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

2021 ◽  
Vol 118 (28) ◽  
pp. e2100171118
Author(s):  
Nicholas J. Kapolka ◽  
Jacob B. Rowe ◽  
Geoffrey J. Taghon ◽  
William M. Morgan ◽  
Corin R. O’Shea ◽  
...  
Keyword(s):  
G Protein ◽  
Coincidence Detection ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Molecular Sensors ◽  
Rich Diversity ◽  
A2a Receptor ◽  
Protein Signaling Networks ◽  
Adenosine A2a ◽  
Physical And Chemical

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.

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

2021 ◽  
Author(s):  
Nicholas J Kapolka ◽  
Jacob B Rowe ◽  
Geoffrey J Taghon ◽  
William M Morgan ◽  
Corin R O'Shea ◽  
...  
Keyword(s):  
G Protein ◽  
Logic Gates ◽  
Coincidence Detection ◽  
Protein Signaling ◽  
New Paradigm ◽  
Gpcr Signaling ◽  
Molecular Logic Gates ◽  
Rich Diversity ◽  
Protein Signaling Networks ◽  
Physical And Chemical

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.

scholarly journals Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A2A Receptor

Structure ◽  
2019 ◽  
Vol 27 (4) ◽  
pp. 703-712.e3 ◽  
Author(s):  
Sangbae Lee ◽  
Anita K. Nivedha ◽  
Christopher G. Tate ◽  
Nagarajan Vaidehi
Keyword(s):  
G Protein ◽  
Adenosine A2a Receptor ◽  
Active State ◽  
A2a Receptor ◽  
Adenosine A2a

scholarly journals A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity

2020 ◽  
Vol 13 (617) ◽  
pp. eaaw5885 ◽  
Author(s):  
Marta Sanchez-Soto ◽  
Ravi Kumar Verma ◽  
Blair K. A. Willette ◽  
Elizabeth C. Gonye ◽  
Annah M. Moore ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Structural Basis ◽  
Protein Signaling ◽  
Ligand Binding Site ◽  
Intracellular Loop ◽  
Gpcr Signaling ◽  
Biased Signaling ◽  
Dynamics Simulations

Signaling bias is the propensity for some agonists to preferentially stimulate G protein–coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein–biased agonist of the D2 dopamine receptor (D2R) that results in impaired β-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbering) functions as a microswitch for regulating receptor interactions with β-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within other GPCRs similarly impaired β-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the β2-adrenergic receptor (β2R) to build β2R-WT and β2R-Y1995.38A models in complex with the full β2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in β2R-Y1995.38A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in β2R-Y1995.38A, which is predicted to affect its interactions with β-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.

scholarly journals Probing the mutational landscape of regulators of G protein signaling proteins in cancer

2020 ◽  
Vol 13 (617) ◽  
pp. eaax8620 ◽  
Author(s):  
Vincent DiGiacomo ◽  
Marcin Maziarz ◽  
Alex Luebbers ◽  
Jillian M. Norris ◽  
Pandu Laksono ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Mammalian Cells ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Loss Of Function ◽  
Gpcr Signaling ◽  
Mutational Landscape ◽  
Binding Interface

The advent of deep-sequencing techniques has revealed that mutations in G protein–coupled receptor (GPCR) signaling pathways in cancer are more prominent than was previously appreciated. An emergent theme is that cancer-associated mutations tend to cause enhanced GPCR pathway activation to favor oncogenicity. Regulators of G protein signaling (RGS) proteins are critical modulators of GPCR signaling that dampen the activity of heterotrimeric G proteins through their GTPase-accelerating protein (GAP) activity, which is conferred by a conserved domain dubbed the “RGS-box.” Here, we developed an experimental pipeline to systematically assess the mutational landscape of RGS GAPs in cancer. A pan-cancer bioinformatics analysis of the 20 RGS domains with GAP activity revealed hundreds of low-frequency mutations spread throughout the conserved RGS domain structure with a slight enrichment at positions that interface with G proteins. We empirically tested multiple mutations representing all RGS GAP subfamilies and sampling both G protein interface and noninterface positions with a scalable, yeast-based assay. Last, a subset of mutants was validated using G protein activity biosensors in mammalian cells. Our findings reveal that a sizable fraction of RGS protein mutations leads to a loss of function through various mechanisms, including disruption of the G protein–binding interface, loss of protein stability, or allosteric effects on G protein coupling. Moreover, our results also validate a scalable pipeline for the rapid characterization of cancer-associated mutations in RGS proteins.

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

MedChemComm ◽  
2013 ◽  
Vol 4 (1) ◽  
pp. 52-67 ◽  
Author(s):  
Stephen P. Andrews ◽  
Benjamin Tehan
Keyword(s):  
Parkinson’S Disease ◽  
Drug Design ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Adenosine A2a Receptor ◽  
Structure Based Drug Design ◽  
A2a Receptor ◽  
Adenosine A2a ◽  
G Protein Coupled

The first example of structure-based drug design with stabilised GPCRs has enabled the identification of a preclinical candidate for the treatment of Parkinson's disease.

Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling

Cell ◽  
2021 ◽  
Author(s):  
Shuya Kate Huang ◽  
Aditya Pandey ◽  
Duy Phuoc Tran ◽  
Nicolas L. Villanueva ◽  
Akio Kitao ◽  
...  
Keyword(s):  
G Protein ◽  
Adenosine A2a Receptor ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
A2a Receptor ◽  
Conformational Landscape ◽  
Adenosine A2a
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