How Do GPCRs Work?
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- Recombinant Proteins
- Native Proteins
- GMP Proteins
- Fluorescent Dyes
- How Do GPCRs Work? Information
- GPCRs Class A
- GPCRs Class B
- GPCRs Class C
- GPCRs Class F
- GPCRs Taste/Vomeronasal Receptors
- Physiological Functions of GPCRs
- How Do GPCRs Work?
- Dysregulation of GPCRs
- GPCRs Desensitization
- GPCRs Diseases
- G-protein coupled receptor (GPCR) pathways
- GPCRs Subfamily
- G-protein Signaling
Ligands/receptors proteins
Interacting Proteins
Inhibitors/promotors
Substrate
Class A rhodopsin-like
Class B secretin-like
Metabotropic glutamate/pheromone
Class F frizzled (FZD)
Other GPCRs
The signaling mechanism of GPCRs is initiated when an extracellular ligand binds to the receptor, which leads to a conformational change in the receptor that allows it to interact with. The binding of ligand-receptor activates an intracellular G-protein. The process of GPCR activation and signaling can be divided down into several key steps:
Step 1: Ligand Binding
The signaling process begins when the ligand binds to the extracellular domain of the GPCR. Ligands act as agonists and can be small molecules (e.g. adrenaline), peptides (e.g. glucagon) or large proteins (e.g. chemokines ). Upon ligand binding, the GPCR undergoes a conformational change, particularly in the transmembrane helices, which is transferred to the intracellular side of the receptor.
Examples of GPCRs that engage in ligand binding include ADRB2, which binds to adrenaline; GLP1R, which interacts with glucagon; and CXCR4, which is activated by chemokines.
Step 2: G-Protein Activation
GPCRs are connected to heterotrimeric G-proteins, which have three parts: alpha (Gα), beta (Gβ), and gamma (Gγ). When inactive, the Gα subunit is bound to GDP (guanosine diphosphate), and the Gαβγ complex associated with the intracellular side of the GPCR. When a ligand activates the GPCR, the GPCR acts as a guanine nucleotide exchange factor (GEF) for the Gα subunit, promoting the exchange of GDP for GTP (guanosine triphosphate). This exchange activates the G-protein by causing dissociation of the Gα subunit from the Gβγ dimer.
Key GPCRs involved in G-protein activation include HTR2A, which binds to Gαq proteins; MC4R, which signals through Gαs; and DRD2, which binds to Gαi for inhibitory responses.
Step 3: Effector Activation
The activated Gα subunit and the free Gβγ dimer can now interact with and regulate various downstream effectors, such as enzymes (e.g., adenylyl cyclase, phospholipase C) and ion channels (e.g., calcium channels, potassium channels). The nature of the downstream signaling response depends on the specific G-protein that is activated. Gα proteins are classified into four main families based on their downstream signaling pathways: Gαs, Gαi, Gαq, and Gα12/13:
- Gαs (stimulatory) activates adenylyl cyclase, which increases the production of cAMP, a second messenger that activates protein kinase A (PKA) and other downstream targets.
- Gαi (inhibitory) inhibits adenylyl cyclase, reducing cAMP levels and downstream signaling.
- Gαq activates phospholipase C (PLC) , which leads to the production of inositol triphosphate (IP3) and diacylglycerol (DAG), triggering calcium release from the endoplasmic reticulum and activating protein kinase C (PKC).
- Gα12/13 regulates small GTPases, such as Rho, involved in cytoskeletal rearrangements and cell motility.
Effector activation is mediated by GPCRs like CASR, which regulates calcium signaling; TAS1R3, which triggers cAMP production; and GPR119, which enhances insulin secretion.
Step 4: Signal Termination and Receptor Desensitization
GPCR signaling is tightly regulated to ensure proper signaling. The process of signal termination begins when the Gα subunit hydrolyzes GTP into GDP. The Gα-GDP subunit then reassociates with the Gβγ dimer, returning the G-protein to its inactive state.
In addition, GPCRs can undergo desensitization after prolonged stimulation. This process is mediated by GPCR kinases (GRKs) that phosphorylate the intracellular loops and C-terminus of the receptor. Phosphorylation promotes the binding of arrestin proteins, which block further G-protein activation and target the receptor for internalization through clathrin-coated pits.
Signal termination and receptor desensitization mechanisms are observed in GPCRs such as SMO, involved in Hedgehog signaling; FZD4, regulating Wnt pathways; and ADRB1, desensitized in response to prolonged adrenergic stimulation.
Fig. 1: G protein-coupled receptor (GPCR) signaling pathway. GPCRs receive signals from various stimuli and transduce the signal through G proteins in the cytosol. G proteins are made up of three subunits (α, β, and γ) and are anchored in the plasma membrane by binding through the α and γ subunits, while GPCRs bind G proteins through the α subunit. In the absence of stimuli, the Gα subunit binds ADP and is inactive. However, upon activation, the α subunit binds ATP and dissociates from the β and γ subunits. There are four different types of Gα subunits (Gαs, Gαi/o, Gαq/11, and Gα12/13), which further relay the signal to downstream targets, ultimately leading to gene transcription. The dissociated Gβ-Gγ dimer also participates in various downstream signaling pathways (Kumari et al ., 2021).
Reference
- Kumari, N., Reabroi, S., & North, B. J. (2021). Unraveling the molecular nexus between GPCRS, ERS, and EMT. Mediators of Inflammation , 2021, 1–23.