Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321193
Author(s):  
Lena Gottesman-Katz ◽  
Rocco Latorre ◽  
Stephen Vanner ◽  
Brian L Schmidt ◽  
Nigel W Bunnett

Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

1994 ◽  
Vol 63 (1) ◽  
pp. 101-132 ◽  
Author(s):  
C D Strader ◽  
T M Fong ◽  
M R Tota ◽  
D Underwood ◽  
R A F Dixon

2004 ◽  
Vol 86 (4) ◽  
pp. 1904-1921 ◽  
Author(s):  
Rene J. Trabanino ◽  
Spencer E. Hall ◽  
Nagarajan Vaidehi ◽  
Wely B. Floriano ◽  
Victor W.T. Kam ◽  
...  

2002 ◽  
Vol 99 (20) ◽  
pp. 12622-12627 ◽  
Author(s):  
N. Vaidehi ◽  
W. B. Floriano ◽  
R. Trabanino ◽  
S. E. Hall ◽  
P. Freddolino ◽  
...  

2019 ◽  
Author(s):  
Eric M. Jones ◽  
Nathan B. Lubock ◽  
AJ Venkatakrishnan ◽  
Jeffrey Wang ◽  
Alex M. Tseng ◽  
...  

AbstractIn humans, the 813 G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state, and are the largest class of drug targets. Their myriad structural conformations and various modes of signaling make it challenging to understand their structure and function. Here we developed a platform to characterize large libraries of GPCR variants in human cell lines with a barcoded transcriptional reporter of G-protein signal transduction. We tested 7,800 of 7,828 possible single amino acid substitutions to the beta-2 adrenergic receptor (β2AR) at four concentrations of the agonist isoproterenol. We identified residues specifically important for β2AR signaling, mutations in the human population that are potentially loss of function, and residues that modulate basal activity. Using unsupervised learning, we resolve residues critical for signaling, including all major structural motifs and molecular interfaces. We also find a previously uncharacterized structural latch spanning the first two extracellular loops that is highly conserved across Class A GPCRs and is conformationally rigid in both the inactive and active states of the receptor. More broadly, by linking deep mutational scanning with engineered transcriptional reporters, we establish a generalizable method for exploring pharmacogenomics, structure and function across broad classes of drug receptors.


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