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Overview of G Protein-Coupled Receptors (GPCRs)

G Protein-Coupled Receptors (GPCRs) are a large family of cell surface receptors that play a crucial role in signal transduction. They respond to various extracellular signals and activate intracellular signaling pathways through the activation of G proteins. GPCRs are involved in numerous physiological processes and are important targets for many drugs.

Structure of GPCRs

• GPCRs have a common structure characterized by:
  • Seven transmembrane alpha-helices.
  • An extracellular N-terminus and an intracellular C-terminus.
  • Three extracellular loops and three intracellular loops.

Mechanism of GPCR Activation

• Ligand Binding:
  • A ligand (e.g., hormone, neurotransmitter, or drug) binds to the extracellular domain of the GPCR.
• G Protein Activation:
  • The ligand-bound GPCR undergoes a conformational change.
  • This change activates the associated G protein by facilitating the exchange of GDP for GTP on the G protein's alpha subunit.
• Signal Transduction:
  • The activated G protein dissociates into alpha and beta-gamma subunits.
  • These subunits interact with various effector proteins (e.g., enzymes or ion channels) to propagate the signal.
• Termination of Signal:
  • The GTP on the alpha subunit is hydrolyzed to GDP, inactivating the G protein.
  • The alpha and beta-gamma subunits reassociate, and the GPCR returns to its resting state.

Types of G Proteins

• G proteins are classified based on the alpha subunit into four main types:
  • Gs (Stimulatory):
    • Activates adenylate cyclase, increasing cyclic AMP (cAMP) levels.
  • Gi (Inhibitory):
    • Inhibits adenylate cyclase, decreasing cAMP levels.
  • Gq:
    • Activates phospholipase C (PLC), leading to the production of inositol trisphosphate (IP₃) and diacylglycerol (DAG).
  • G12/13:
    • Regulates cytoskeletal remodeling and cell migration.

Functions of GPCRs

• Sensory Perception:
  • GPCRs are involved in vision (e.g., rhodopsin in photoreceptors), smell (olfactory receptors), and taste (taste receptors).
• Neurotransmission:
  • GPCRs mediate the effects of many neurotransmitters, such as serotonin, dopamine, and acetylcholine.
• Immune Response:
  • GPCRs regulate immune cell migration and activation (e.g., chaemokine receptors).
• Cell Growth and Differentiation:
  • GPCRs are involved in the regulation of cell growth, proliferation, and differentiation.
• Cardiovascular Function:
  • GPCRs regulate heart rate, vascular tone, and blood pressure (e.g., adrenergic receptors).

Clinical Relevance

• Pharmacological Targets:
  • Many drugs target GPCRs to treat conditions such as hypertension, heart failure, asthma, and psychiatric disorders.
  • Examples include beta-blockers (adrenergic receptors), antipsychotics (dopamine receptors), and antihistamines (histamine receptors).
• Genetic Mutations:
  • Mutations in GPCRs or G proteins can lead to various diseases, including cancer, congenital disorders, and metabolic syndromes.
• Drug Development:
  • GPCRs are a major focus in drug development due to their involvement in numerous physiological processes and diseases.
  • Novel therapies targeting GPCRs are being explored for cancer, obesity, diabetes, and neurodegenerative diseases.

Summary

G Protein-Coupled Receptors (GPCRs) are critical for cellular communication and play essential roles in various physiological processes. They function by transducing extracellular signals into intracellular responses through the activation of G proteins. Understanding the structure, function, and clinical relevance of GPCRs is crucial for developing targeted therapies for numerous diseases.