Related Experiment Video
Updated: Jun 20, 2026
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Multiple switches in G protein-coupled receptor activation.
Shivani Ahuja1, Steven O Smith
1Department of Physics and Astronomy and Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Trends in Pharmacological Sciences
|September 8, 2009
Summary
G protein-coupled receptor activation involves multiple structural "switches" that must align, a mechanism termed "coincidence counting." This explains how receptors respond to diverse signals and agonist differences.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- G protein-coupled receptors (GPCRs) are crucial cell surface receptors with a conserved seven-transmembrane helix structure.
- Despite their simple architecture, GPCRs mediate diverse signaling pathways in response to various stimuli, including light and ligands.
- The precise activation mechanism of GPCRs has remained incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying G protein-coupled receptor activation.
- To investigate the role of structural rearrangements in receptor signaling.
- To explain the basis for differential agonist efficacy (full, partial, inverse).
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy of the active metarhodopsin II intermediate.
- X-ray crystallography of the apoprotein opsin.
- Structural analysis of conserved amino acids and transmembrane helices.
Main Results:
- Identified multiple structural elements or "switches" within GPCRs that undergo conformational changes upon activation.
- Demonstrated that simultaneous triggering of these switches is required for full receptor activation.
- Proposed a "coincidence counting" model where multiple events converge for activation.
Conclusions:
- GPCR activation is regulated by a "coincidence counting" mechanism involving the coordinated action of multiple structural switches.
- This mechanism provides a framework for understanding the diverse responses of GPCRs to various ligands.
- The presence of multiple switches may explain the observed differences in efficacy among full, partial, and inverse agonists.
Related Concept Videos
01:22Activation and Inactivation of G Proteins
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 affinity and are together...
01:30Transducer Mechanism: G Protein–Coupled Receptors
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, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...
01:15G Protein-coupled Receptors
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...
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...
01:15G Protein-coupled Receptors
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...
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...
01:21G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
01:21G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.