G Protein Coupled Receptors

Introduction

• G Protein Coupled Receptors (GPCRs): Also known as seven-pass receptors or serpentine receptors since they pass through the membrane seven times, resembling a snake-like structure.

Structure and Domains

1. Structure: These receptors pass through the cell membrane seven times.
2. Domains:
   • Ligand binding domain: Located extracellularly, where specific molecules bind.
   • Effector domain: Located intracellularly, responsible for eliciting a biological response when the receptor is activated.

Functions of GPCRs

• Activation: Binding of a ligand to the ligand-binding domain causes a conformational change in the receptor, exposing the effector domain to interact with intracellular molecules.
• Signaling Pathway: Often involves interaction with G proteins (trimeric G proteins) to transduce the signal inside the cell.

Types of G Proteins

• Monomeric G Proteins: Consist of a single peptide.
• Trimeric G Proteins: Consist of three peptides (alpha, beta, gamma) and interact with GPCRs.

Categories of Receptors

Membrane Receptors

1. One-pass receptors: e.g., Insulin and growth factor receptors.
2. Four-to-five-pass receptors: Ligand-gated ion channels (e.g., nicotinic cholinergic receptors).
3. Seven-pass receptors (GPCRs): e.g., Adrenergic, muscarinic cholinergic, and dopaminergic receptors.
4. Twelve-pass receptors: e.g., Monoamine neurotransmitter reuptake receptors.

Intracellular Receptors

• Cytosolic and Nuclear Receptors: Small or lipid-soluble ligands can cross the membrane and bind to these receptors (e.g., estrogen receptors in the cytosol, T3 receptors in the nucleus).

Extracellular Receptors

• Coagulation factors: e.g., Antithrombin III, which interacts with heparin.
• Cytokines and complement proteins (like C5a).

Important Concepts

1. Inactivation vs. Desensitization: Different mechanisms by which receptor activity can be reduced. Inactivation renders the receptor non-functional, whereas desensitization typically allows it to be re-sensitized later.
2. Downregulation and Upregulation: Changes in receptor numbers on the cell surface due to prolonged exposure to ligands or changes in receptor synthesis/degradation.
3. Functional Domains Requirements: Must include ligand-binding and effector domains.

Key Functions and Regulatory Mechanisms

• Activation: Ligand binding activates G proteins, which then trigger a cascade of intracellular events (second messenger pathways like cyclic AMP changes).
• Desensitization: Prolonged exposure to agonists can lead to reduced receptor responsiveness.
• Re-Sensitization: The process by which desensitized receptors regain responsiveness.
• Downregulation: A decrease in receptor number on the cell surface, often due to prolonged ligand exposure.
• Upregulation: An increase in receptor number, often due to receptor synthesis.

Clinical Relevance

• Around 30-40% of available drugs target GPCRs, making their study crucial for understanding drug mechanisms and therapeutic effects.
• Examples include treatments for hypertension, cardiac conditions, and some psychiatric disorders.

Summary and Future Topics

In the next lecture, topics will include:

• Detailed mechanisms of GPCR activation and inactivation.
• Distinction between agonist, antagonist, and partial agonist/antagonist drugs.
• Mechanism of receptor desensitization and re-sensitization.
• Overview of receptor downregulation and upregulation.