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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
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GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Nociception01:44

Nociception

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Nociception—the ability to feel pain—is essential for an organism’s survival and overall well-being. Noxious stimuli such as piercing pain from a sharp object, heat from an open flame, or contact with corrosive chemicals are first detected by sensory receptors, called nociceptors, located on nerve endings. Nociceptors express ion channels that convert noxious stimuli into electrical signals. When these signals reach the brain via sensory neurons, they are perceived as pain.
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G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
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GPR68, A Proton-sensing GPCR, Mediates Acid-induced Visceral Nociception.

Luke W Paine1, Rohit Gupta1, James P Higham1

  • 1Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.

Cellular and Molecular Gastroenterology and Hepatology
|November 6, 2025
PubMed
Summary

Acid-sensing receptor G protein-coupled receptor 68 (GPR68) mediates pain in colitis. Blocking GPR68 reduces acid-evoked colonic sensory signaling, offering a potential therapeutic target for colitis pain.

Keywords:
ColitisNociceptorsPainVisceral Hypersensitivity

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Area of Science:

  • Gastroenterology and Immunology
  • Neuroscience
  • Molecular Biology

Background:

  • Localised acidification and heightened glycolysis contribute to colitis pathology by activating acid-sensing receptors.
  • G protein-coupled receptor 68 (GPR68), a proton-sensing receptor, is expressed on immune and stromal cells.
  • Single-cell RNA sequencing revealed GPR68 expression in colonic sensory neurons, suggesting a role in pain signaling.

Purpose of the Study:

  • Investigate the role of GPR68 in acid-induced colonic nociception.
  • Determine GPR68's contribution to colitis pathology and pain.
  • Evaluate GPR68 as a potential therapeutic target for colitis-associated pain.

Main Methods:

  • In silico analysis of RNA-sequencing data to confirm GPR68 expression in colonic nociceptors and human colitis tissue.
  • Assessment of GPR68's role in disease activity using the dextran sulphate sodium (DSS) model of colitis in GPR68 knockout mice.
  • Evaluation of acid-evoked sensory signaling via colonic afferent recordings and calcium imaging in dorsal root ganglion (DRG) neurons.
  • Pharmacological studies using a GPR68 positive allosteric modulator (Ogerin) and antagonist (Ogremorphin).

Main Results:

  • GPR68 is highly expressed in Trpv1+ colonic nociceptors and upregulated in inflammatory bowel disease tissue.
  • GPR68 knockout mice exhibited reduced disease activity in the DSS model.
  • Genetic deletion or pharmacological antagonism of GPR68 abolished or attenuated acid-evoked colonic afferent responses and DRG neuron calcium signaling.
  • GPR68 deletion did not affect capsaicin-evoked responses, indicating specific involvement in proton-dependent signaling.

Conclusions:

  • GPR68 is a key mediator of acid-induced colonic nociception.
  • GPR68 plays a significant role in the pain associated with colitis.
  • GPR68 represents a promising therapeutic target for managing pain in colitis patients.