Related Experiment Video
Updated: Aug 7, 2025
10:13
Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
16.5K
Autoregulation of GPCR signalling through the third intracellular loop.
Fredrik Sadler1,2, Ning Ma3,4, Michael Ritt2
1Biochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis, MN, USA.
Nature
|March 8, 2023
Summary
The third intracellular loop (ICL3) of G protein-coupled receptors (GPCRs) regulates signaling by controlling G protein binding. This loop acts as an allosteric site, influencing receptor activity and specificity across the GPCR superfamily.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The third intracellular loop (ICL3) is crucial for G protein-coupled receptor (GPCR) signal transduction.
- ICL3's structural complexity and sequence variability hinder understanding of its role in GPCR signaling.
- Previous research implicated ICL3 in the structural dynamics of beta-2 adrenergic receptor (β2AR) activation and signaling.
Purpose of the Study:
- To elucidate the mechanistic role of ICL3 in β2AR signaling.
- To investigate how ICL3 influences receptor activation and G protein binding.
- To explore the broader implications of ICL3 function across the GPCR superfamily.
Main Methods:
- Investigated the dynamic conformational equilibrium of ICL3.
- Examined the interaction between ICL3 and the G protein-binding site.
- Utilized G protein-mimetic effectors to probe receptor allosteric activation.
- Assessed ICL3's role in G protein subtype selectivity.
Main Results:
- ICL3 dynamically regulates GPCR activity by modulating the G protein-binding site accessibility.
- G protein-mimetic ligands allosterically activate the receptor by biasing ICL3 towards exposed states.
- ICL3 inhibits coupling to weakly interacting G protein subtypes, tuning signaling specificity.
- This ICL3-mediated negative G protein selection mechanism is conserved across GPCRs.
Conclusions:
- ICL3 autoregulates GPCR activity through a conformational equilibrium.
- ICL3 is essential for receptor pharmacology, mediating allosteric activation and signaling specificity.
- The findings reveal a conserved mechanism of G protein subtype selection by ICL3.
- ICL3 represents a potential allosteric site for developing novel, pathway-specific ligands.
More Related Videos
07:41A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
9.0K
09:40Imaging G-protein Coupled Receptor GPCR-mediated Signaling Events that Control Chemotaxis of Dictyostelium Discoideum
Published on: September 20, 2011
18.0K
Related Concept Videos
01:09GPCRs Regulate Adenylyl Cylase Activity
5.7K
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...
5.7K
01:11IP3/DAG Signaling Pathway
12.2K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
12.2K
01:21G-protein Coupled Receptors
120.7K
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.
120.7K
01:12GPCR Desensitization
6.2K
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...
6.2K
01:22Amplifying Signals via Enzymatic Cascade
8.6K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.6K
01:15Amplifying Signals via Second Messengers
7.1K
Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
7.1K