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Related Concept Videos

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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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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G Protein-coupled Receptors01:15

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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.
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G-Protein Gated Ion Channels01:21

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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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Activation and Inactivation of G Proteins01:22

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Related Experiment Video

Updated: Apr 30, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

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Allosteric sodium in class A GPCR signaling.

Vsevolod Katritch1, Gustavo Fenalti1, Enrique E Abola1

  • 1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Trends in Biochemical Sciences
|April 29, 2014
PubMed
Summary

Sodium ions are crucial for G-protein-coupled receptors (GPCRs) function. New research reveals how sodium binding within the seven-transmembrane domain influences GPCR activation and allosteric modulation.

Keywords:
GPCR activationallosteric modulationbiased signalingconserved pocketsodium ionwater binding

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • G-protein-coupled receptors (GPCRs) are vital cell surface receptors involved in diverse physiological processes.
  • GPCRs mediate signal transduction through conformational changes in their seven-transmembrane (7TM) helical domain.
  • The precise molecular mechanisms governing GPCR activation remain an active area of research.

Purpose of the Study:

  • To review recent crystallographic findings on sodium ion binding within the 7TM bundle of class A GPCRs.
  • To discuss the structural characteristics and functional implications of the sodium-binding pocket.
  • To elucidate the role of sodium in GPCR allosteric modulation and activation.

Main Methods:

  • Analysis of recent crystallographic data for multiple class A GPCRs.
  • Structural comparison of sodium-binding pockets across different GPCRs.
  • Review of literature on sodium's allosteric effects on GPCRs.

Main Results:

  • A conserved, partially hydrated sodium ion is specifically bound within the 7TM bundle of numerous class A GPCRs.
  • The sodium-binding pocket exhibits both structural conservation and distinct features across this GPCR class.
  • Receptor activation is associated with a conformational collapse of the sodium-binding pocket.
  • Sodium binding allosterically influences GPCR agonist binding and receptor activation.

Conclusions:

  • Sodium ions play a significant role in the structure and function of class A GPCRs.
  • The sodium-binding pocket and its conformational changes are integral to GPCR signal transduction.
  • Sodium acts as a potential co-factor, modulating GPCR activity and offering therapeutic targets.