Related Experiment Video
Updated: Jan 28, 2026
11:45
Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
19.8K
Regulating G protein-coupled receptors by topological inversion.
Bray Denard1, Sungwon Han1, JungYeon Kim1
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
Elife
|March 6, 2019
Summary
Sphingolipids like ceramide can alter the structure of G protein-coupled receptors (GPCRs), affecting cell signaling. This topological inversion, observed in CCR5, impacts immune cell migration in response to stimuli like lipopolysaccharide (LPS).
Area of Science:
- Molecular Biology
- Cellular Signaling
- Immunology
Background:
- G protein-coupled receptors (GPCRs) are integral membrane proteins with a conserved seven-transmembrane helix structure.
- The topology of GPCRs, with N-terminus extracellular and C-terminus cytoplasmic, is crucial for their function.
- Sphingolipids, including ceramides, are key membrane components involved in cellular regulation.
Purpose of the Study:
- To investigate the potential for ceramides and related sphingolipids to alter GPCR topology.
- To elucidate the functional consequences of GPCR topological inversion using the CCR5 receptor as a model.
- To understand the role of lipopolysaccharide (LPS) in modulating GPCR topology and cellular response.
Main Methods:
- Analysis of GPCR topology, focusing on the GXXXN motif in the first transmembrane helix.
- Experimental manipulation of ceramide and dihydroceramide levels.
- Assessment of macrophage migration in response to chemokine ligands (CCL5) under varying conditions (e.g., LPS stimulation).
Main Results:
- Ceramides and related sphingolipids can induce topological inversion in GPCRs possessing a specific motif.
- Lipopolysaccharide (LPS) stimulation increases dihydroceramide, leading to CCR5 topological inversion.
- Inverted CCR5 topology prevents macrophage migration towards its ligand CCL5, demonstrating functional significance.
Conclusions:
- GPCR topology is not static and can be dynamically regulated by sphingolipids.
- Topological inversion of GPCRs represents a novel mechanism for controlling cellular responses.
- This finding has implications for understanding immune cell behavior and signaling pathways.
Related Concept Videos
01:21G-protein Coupled Receptors
131.9K
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.
131.9K
01:15G Protein-coupled Receptors
16.8K
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...
16.8K
01:30Transducer Mechanism: G Protein–Coupled Receptors
4.1K
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,...
GPCRs are also called heptahelical,...
4.1K
02:58Regulated Protein Degradation
8.8K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
8.8K
02:58Regulated Protein Degradation
3.2K
3.2K
02:04Covalently Linked Protein Regulators
9.2K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
9.2K