G-Protein-Coupled Receptors

G-Protein-Coupled Receptors

• G-protein-coupled receptors act indirectly to regulate the activity of a separate plasma membrane-bound target protein: an enzyme or an ion channel.
• The interaction between the receptor and the target protein is mediated by a trimeric GTP-binding protein (G protein).
• G-protein-coupled receptors are a large family of homologous, seven-pass transmembrane proteins.
• There are over 1000 G-protein-coupled receptors identified, including receptors for many neurotransmitters, neuropeptides, peptide hormones, eicosanoids, smell, sight, and taste receptors.

G Proteins

• G proteins (trimeric) act as intermediary molecules between receptors and target molecules.
• G proteins are composed of 3 subunits: α, β, and γ subunits (heterotrimeric).
• The α subunit binds both GTP and GDP.
• In the resting state, the α subunit has GDP bound and binds to the β and γ subunits to form a trimeric complex.
• In the active state, the α subunit releases its bound GDP and binds GTP, leading to the separation of the α subunit from the β and γ subunits.

G-Protein-Coupled Receptors and G Proteins

• G proteins regulate the activity of target enzymes or ion channels.
• G proteins activate or inhibit target enzymes, such as adenylyl cyclase (e.g., epinephrine receptor) or ion channels (e.g., heart muscle).
• The binding of an extracellular signal molecule to a G-protein-coupled receptor leads to the activation of adenylyl cyclase and a rise in cyclic AMP concentration.

Enzyme-Linked Receptors

• Enzyme-linked receptors are single-pass transmembrane proteins that are activated by dimerization.
• Ligand binding domains are outside the cell membrane, and the catalytic parts of the receptor are in the cytosol.
• These receptors either act directly like an enzyme or interact with other enzymes inside the cell and stimulate other pathways.

Receptor Tyrosine Kinases

• Receptor tyrosine kinases are a type of enzyme-linked receptor that activate target proteins by binding phosphorus (phosphorylation) to terminal amino acids such as serine, threonine, or tyrosine.
• There are different types of protein kinase receptors, including protein-tyrosine kinase receptors (e.g., insulin receptor, EGF receptor), cytokine receptors, and non-receptor tyrosine kinases.
• The insulin receptor is a protein tyrosine kinase receptor that acts through receptor tyrosine kinases.

Mechanism of Action of Receptor Tyrosine Kinases

• Binding of a ligand (e.g., growth factor) induces receptor dimerization, leading to autophosphorylation of the receptor.
• Autophosphorylation increases protein kinase activity and creates specific binding sites for additional proteins that transmit signals.
• Proteins containing SH2 (Src homology 2) domains or PTB (phosphotyrosine binding) domains associate with phosphorylated cytoplasmic tail of receptors, leading to the activation of downstream signaling pathways.

Ras Signaling Pathway

• Receptor tyrosine kinases activate the Ras signaling pathway, which stimulates cell proliferation and differentiation.
• Ras is a small G protein (monomeric) that binds to GTP and exists in an active state.
• Mutant Ras proteins can not dissociate from GTP and remain in the active state, leading to uncontrolled cell proliferation.
• Defects in receptor tyrosine kinases and related genes are of great importance in cancer, as excessive activation of RTKs results in uncontrolled cell division and tumor development.