G-protein coupled receptors (GPCR)
What is GPCR?
G protein-coupled receptors (GPCRs) are a class of transmembrane proteins widely present in organisms, and they participate in the regulation of various physiological processes and signal transduction pathways. GPCRs bind to extracellular signaling molecules to trigger a series of intracellular signaling events, thereby regulating cell function and behavior.
What these receptors have in common is that there are seven transmembrane α-helices in their three-dimensional structure, and the C-terminus of the peptide chain and the intracellular junction (counting from the N-terminus of the peptide chain) of the 5th and 6th transmembrane helices The loop (the third intracellular loop) has binding sites for the G protein (guanylate-binding protein). So far, studies have shown that G protein-coupled receptors are only found in eukaryotes and are involved in many cell signal transduction processes. During these processes, G protein-coupled receptors can bind chemicals in the cell's surrounding environment and activate a series of signaling pathways in the cell, ultimately causing changes in the cell state.
Based on the results of sequence analysis of the human genome, nearly a thousand G protein-coupled receptor genes have been predicted. These G protein-coupled receptors can be divided into six types, and there is no homologous relationship between the gene sequences of the G protein-coupled receptors belonging to them.
- Class A (or class I, rhodopsin-like receptors)
- Class B (or class II, secretin receptor family)
- Class C (or class III, metabotropic glutamate receptors)
- Class D (or class IV, fungal mating pheromone receptors)
- Class E (or class V, cyclic AMP receptors)
- Class F (or Class VI, Frizzled/Smoothened family)
The first class, the rhodopsin-like receptors, contains the vast majority of G protein-coupled receptors. It is further divided into 19 subclasses A1-A19. Recently, a new classification system for G protein-coupled receptors was proposed, called GRAFS, namely Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin (Secretin) English acronym.
Some bioinformatics-based studies have focused on predicting the classification of G protein-coupled receptors whose specific functions are not yet clear. Using a method called pseudoamino acid composition, the researchers used the amino acid series of G protein-coupled receptors to predict their likely function and classification in vivo.
Structure of GPCR
GPCRs (G protein-coupled receptors) have a similar structural organization, often consisting of a single protein. They are seven-segment transmembrane proteins with an N-terminus (extracellular) and a C-terminus (intracellular), connected by seven transmembrane helices.
Structurally, GPCRs can be divided into three main regions: the N-terminal outer region, the transmembrane region, and the C-terminal inner region.
The N-terminal external region contains many important functional domains, such as signal peptide, glycosylation site and ligand binding site. These functional domains are critical for ligand recognition and binding of the receptor.
The transmembrane region consists of seven transmembrane helices that are embedded in the cell membrane and form a channel that allows signaling molecules to pass through. These transmembrane helices stabilize the structure through interactions such as hydrogen bonds, ionic interactions, and van der Waals forces, and provide specific spaces to interact with signaling molecules.
The C-terminal inner region is located on the cytoplasmic side and interacts with intracellular signal transduction pathways. These regions contain multiple domains and protein binding sites for activation of signal transduction cascades within the cell.
Clinical Significance of GPCRs
GPCRs are clinically important because they play key roles in the initiation and progression of many diseases. The following are the clinical significance of some GPCRs:
- Drug target: GPCR is one of the important targets for drug development. The mechanism of action of about 30% of marketed drugs is related to GPCR. Many commonly used drugs, such as β-blockers, calcium channel blockers, and renin-angiotensin system inhibitors, treat cardiovascular diseases, hypertension, and other diseases by acting on GPCRs.
- Nervous system diseases: Many neurological diseases, such as Parkinson's disease, Alzheimer's disease and depression, are associated with abnormal function of GPCRs. By studying and modulating GPCRs associated with these diseases, new drugs can be developed to treat and manage these diseases.
- Immunomodulation: Certain GPCRs play an important role in the immune system, regulating the activation, migration and inflammatory response of immune cells. By regulating the activity of these GPCRs, the immune response can be modulated and new immunomodulatory drugs can be developed to treat autoimmune and inflammatory diseases.
- Tumor therapy: Some GPCRs play an important role in the occurrence and progression of tumors. By studying and regulating tumor-associated GPCRs, new drugs can be developed to inhibit tumor cell proliferation, promote apoptosis or block tumor cell migration and invasion.
- Individualized drug therapy: Due to the differences in the responses of different individuals to drugs, individualized drug therapy has become an important research direction. The diversity of GPCRs and their roles in drug metabolism and efficacy make them potential targets for personalized drug therapy. By studying individual GPCR genotypes and expression patterns, drug treatment regimens can be optimized to improve therapeutic efficacy and reduce adverse reactions.
GPCR and the drug target
GPCRs (G protein-coupled receptors) are a major class of drug targets because they play a crucial role in cell signaling and are involved in a wide range of physiological processes. These receptors play a central role in mediating cellular responses to a variety of extracellular signals, including hormones, neurotransmitters, and sensory stimuli. Their ability to transmit signals across cell membranes makes them attractive targets for therapeutic intervention.
Many drugs targeting specific GPCRs have been developed to modulate their activity and affect downstream signaling pathways. These drugs can act as agonists, activating the receptor and mimicking the action of the endogenous ligand, or as antagonists, blocking receptor activation by competing with the natural ligand. By targeting specific GPCRs, drugs can modulate cellular processes and physiological functions, providing potential therapeutic benefit in various disease conditions.
GPCR-targeted drugs have been successfully used to treat a variety of diseases, including cardiovascular diseases, neurological diseases, psychiatric diseases, endocrine diseases, and immune-related diseases. For example, beta-blockers that target beta-adrenergic receptors are widely used to treat high blood pressure and heart disease. Antipsychotic drugs, such as dopamine receptor antagonists, are used to treat schizophrenia and other mental illnesses. Opioid receptors are targeted by pain relievers and histamine receptors are targeted by antihistamines to control allergies.
Ligands/Receptors Proteins Gene Symbols
| CCL11 | CCL5 | CXCL9 |
| CXCL11 | CXCL13 | ADCY1 |
| CCL26 | KPNA1 | ADRBK1 |
| SRC | CALM1 | CALM3 |
| CCL24 |
Interacting Proteins Gene Symbols
| CCL11 | CCL5 | CXCL9 |
| CXCL11 | CXCL13 | ADCY1 |
| CCL26 | KPNA1 | ADRBK1 |
| SRC | CALM1 | CALM3 |
| CCL24 |
Inhibitors/Promotors Gene Symbols
| CCL11 | CCL5 | CXCL9 |
| CXCL11 | CXCL13 | ADCY1 |
| CCL26 |
Substrate Gene Symbols
| CCL11 | CCL5 |
Class A Rhodopsin-like Gene Symbols
| C5AR1 | ADORA3 | CCR2 | CNR1 | DARC | DRD1 |
| EDNRA | EDNRB | FPR1 | GHSR | GRPR | HCRTR2 |
| HRH2 | HTR2B | HTR5A | HTR7 | MC1R | MC4R |
| OPRK1 | P2RY6 | PTGIR | ADRB1 | ADRB2 | HRH1 |
| CX3CR1 | HTR2C | DRD2 | LTB4R | F2R | MTNR1A |
| GPR12 | PTGDR |
Class B Secretin-like Gene Symbols
| CD97 | CALCR | GHRHR |
| GPR125 | CRHR1 |
Metabotropic Glutamate/Pheromone Gene Symbols
| GRM1 | GRM3 | GRM8 |
Class F frizzled (FZD) Gene Symbols
| Fzd1 | Fzd2 | Fzd5 |
| Fzd7 | SMO | Fzd10 |
| Fzd4 |
Other GPCRs
| ADCYAP1R1 | CASR | CXCR3 |
| FPR2 | S1PR1 | S1PR3 |
| CXCR2 | Taar1 | GABBR1 |
References:
[1] Neumann, E., Khawaja, K. & Müller-Ladner, U. G protein-coupled receptors in rheumatology. Nat Rev Rheumatol 10, 429–436 (2014). https://doi.org/10.1038/nrrheum.2014.62
