The Diverse and Versatile GPCR Superfamily

This chapter will introduce you to the fascinating world of G-protein-coupled receptors (GPCRs), the largest and most diverse superfamily of membrane receptors. GPCRs play essential roles in various physiological processes, including vision, olfaction, taste, and neurotransmission. Understanding the mechanisms underlying GPCR coupling selectivity is crucial for developing novel therapeutic strategies and expanding our knowledge of cellular signaling.

First Half: Introduction to GPCRs and Their Structural Features

1.1: Introduction to G Protein-Coupled Receptors (GPCRs)

Summary: GPCRs are a family of membrane receptors that play a crucial role in cellular signaling. They are responsible for detecting various extracellular signals, including neurotransmitters, hormones, and sensory stimuli, and converting them into intracellular responses. GPCRs are involved in numerous physiological processes, including vision, olfaction, taste, and neurotransmission. They are also implicated in various diseases, making them attractive targets for drug development.

1.2: Structural Features of GPCRs

Summary: GPCRs are integral membrane proteins that consist of seven transmembrane (TM) domains connected by three extracellular loops (ECLs) and three intracellular loops (ICLs). The N-terminus of the receptor is located extracellularly, while the C-terminus is located intracellularly. The TM domains contain highly conserved motifs, such as the DRY and NPxxY motifs, which are essential for receptor function.

1.3: Classification of GPCRs Based on Sequence Homology and Phylogenetic Analysis

Summary: GPCRs are classified into six main classes based on sequence homology and phylogenetic analysis. These classes include Class A (rhodopsin-like), Class B (secretin-like), Class C (metabotropic glutamate and GABA-A), Class D (pheromone), Class E (cAMP), and Class F (frizzled/smoothened). Each class has unique structural and functional features, and the ligands that bind to them differ in their chemical and physical properties.

1.4: The Role of GPCRs in Cellular Signaling

Summary: GPCRs transmit signals from the extracellular environment to the intracellular milieu, leading to various cellular responses. GPCR signaling involves a complex network of interactions between the receptor, G proteins, and downstream effectors. The activation of GPCRs leads to the activation of various signaling pathways, including the cAMP, IP3/DAG, and phospholipase C pathways.

Second Half: Activation Mechanisms and Ligands of GPCRs

2.1: General Mechanisms of GPCR Activation

Summary: GPCR activation involves a series of conformational changes in the receptor that lead to the activation of downstream signaling pathways. Agonists bind to the receptor's orthosteric site, leading to the activation of the receptor. Antagonists bind to the receptor's orthosteric site, preventing the binding of agonists and inhibiting receptor activation. Allosteric modulators bind to the receptor's allosteric site, modulating receptor activation in a ligand-specific manner.

2.2: Class A (Rhodopsin-like) GPCRs and Their Ligands

Summary: Class A GPCRs are the largest and most diverse class of GPCRs. They are activated by a wide range of ligands, including neurotransmitters, hormones, and sensory stimuli. Class A GPCRs share a common structural motif, consisting of seven TM domains, three ECLs, and three ICLs. The activation of Class A GPCRs leads to the activation of various signaling pathways, including the cAMP, IP3/DAG, and phospholipase C pathways.

2.3: Class B (Secretin-like) GPCRs and Their Ligands

Summary: Class B GPCRs are activated by peptide hormones and other large molecules. They share a common structural motif, consisting of seven TM domains, a large N-terminal extracellular domain, and three ECLs. The activation of Class B GPCRs leads to the activation of various signaling pathways, including the cAMP and phospholipase C pathways.

2.4: Class C (Metabotropic Glutamate and GABA-A) GPCRs and Their Ligands

Summary: Class C GPCRs are activated by neurotransmitters, such as glutamate and GABA. They share a common structural motif, consisting of seven TM domains, a large N-terminal extracellular domain, and three ECLs. The activation of Class C GPCRs leads to the activation of various signaling pathways, including the cAMP and IP3/DAG pathways.

2.5: Class D (Pheromone) GPCRs and Their Ligands

Summary: Class D GPCRs are activated by pheromones, which are chemical signals that play crucial roles in various organisms' communication and mating behaviors. They share a common structural motif, consisting of seven TM domains, three ECLs, and three ICLs. The activation of Class D GPCRs leads to the activation of various signaling pathways, including the cAMP and phospholipase C pathways.

2.6: Class F (Frizzled/Smoothened) GPCRs and Their Ligands

Summary: Class F GPCRs are activated by Wnt proteins, which are signaling molecules involved in developmental processes and tissue homeostasis. They share a common structural motif, consisting of seven TM domains, three ECLs, and three ICLs. The activation of Class F GPCRs leads to the activation of various signaling pathways, including the Wnt/β-catenin and Wnt/planar cell polarity pathways.

Key Points

  • GPCRs are a family of membrane receptors that play a crucial role in cellular signaling.
  • GPCRs are classified into six main classes based on sequence homology and phylogenetic analysis.
  • GPCR activation involves a series of conformational changes in the receptor that lead to the activation of downstream signaling pathways.
  • Agonists bind to the receptor's orthosteric site, leading to the activation of the receptor, while antagonists bind to the receptor's orthosteric site, preventing the binding of agonists and inhibiting receptor activation.
  • Allosteric modulators bind to the receptor's allosteric site, modulating receptor activation in a ligand-specific manner.
  • Class A GPCRs are the largest and most diverse class of GPCRs, activated by a wide range of ligands, including neurotransmitters, hormones, and sensory stimuli.
  • Class B GPCRs are activated by peptide hormones and other large molecules.
  • Class C GPCRs are activated by neurotransmitters, such as glutamate and GABA.
  • Class D GPCRs are activated by pheromones, which are chemical signals that play crucial roles in various organisms' communication and mating behaviors.
  • Class F GPCRs are activated by Wnt proteins, which are signaling molecules involved in developmental processes and tissue homeostasis.