GPCRs (G Protein Coupled Receptors): A Guide

GPCR ligands encompass various types that interact with GPCRs. The vast majority of GPCRs are activated by small-molecule ligands, including hormones, neurotransmitters, and chemokines. Hormones, such as peptides, steroids, and eicosanoids, are the most common type of GPCR ligand. Neurotransmitters, such as acetylcholine, dopamine, serotonin, and norepinephrine, play a crucial role in mediating communication between neurons. Chemokines, a family of small proteins, regulate leukocyte trafficking. Additionally, some GPCRs are activated by photons, specifically responding to light stimuli.

GPCR signaling is a complex process involving the activation of G proteins by GPCRs and other receptors, such as the Toll-like receptor (TLR) family. Upon ligand binding, GPCRs undergo conformational changes that induce the activation of associated G proteins. This activation triggers a conformational change in the G protein, enabling it to exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The GTP-bound α subunit dissociates from the βγ subunits, allowing both subunits to interact with downstream effectors, such as enzymes or ion channels.

1. Receptor activation: When an external signaling molecule binds to a GPCR, it causes conformational changes in the receptor, leading to the activation of associated G proteins. This interaction initiates the GPCR signaling pathway.

2. Signaling cascade initiation: The activated G protein interacts with downstream effectors, activating them in turn. This cascade of signaling events amplifies the cellular response and propagates the signal further within the cell.

3. Effector activation: Effector activation is the final stage of the GPCR pathway, resulting in the cellular response to the initial signal. The specific response depends on the nature of the signaling molecule and the target cell. Agonist ligands typically lead to cell activation, while antagonist ligands usually result in cell inhibition.

The α subunit, in its active GTP-bound form, modulates the activity of these effectors, leading to the generation of intracellular second messengers or the initiation of signaling cascades. The βγ subunits can also independently regulate various intracellular processes. Eventually, the GTP on the α subunit is hydrolyzed to GDP, leading to the reassociation of the α and βγ subunits and the termination of signaling.

This highly orchestrated GPCR signaling pathway plays a critical role in transmitting extracellular signals to intracellular processes, influencing diverse physiological responses in cells and tissues. The specific effects of GPCR signaling depend on the type of G protein and its downstream targets, including enzymes, ion channels, and other membrane components involved in cellular communication.

The regulation of GPCR signaling is a complex process involving multiple mechanisms that ensure tight control and fine-tuning of cellular responses. One important process is desensitization, where continuous or prolonged stimulation of GPCRs leads to reduced receptor responsiveness. This is achieved through receptor phosphorylation by kinases like G protein-coupled receptor kinases (GRKs) and subsequent binding of arrestins, which inhibit further G protein activation. Another regulatory mechanism is internalization, wherein the activated receptors are internalized from the cell surface into intracellular compartments, modulating their availability for signaling. Additionally, GPCRs undergo processes like receptor sequestration, recycling, and degradation, which contribute to the fine-tuning and termination of signaling events. These regulatory mechanisms play crucial roles in maintaining cellular homeostasis and ensuring appropriate responses to extracellular stimuli.

GPCRs play pivotal roles in a wide range of physiological functions due to their widespread distribution and ability to trigger cellular responses to various extracellular stimuli. These receptors mediate sensory information, including pheromone sensation, olfaction, light perception, and taste. In fact, about half of the 800 GPCRs are involved in sensory functions. Additionally, more than 90% of GPCRs are expressed in the brain, where they participate in crucial processes related to mood, cognition, pain, appetite, and contribute to numerous neurodegenerative and psychiatric disorders. Moreover, GPCRs are essential components of the immune system, regulating immune cell differentiation, migration, and the secretion of antimicrobial compounds. Their aberrant expression or activation is associated with autoimmune diseases and immunodeficiencies. GPCRs also play roles in cancer progression, influencing tumor cell proliferation, invasion, migration, and metastasis. Their involvement extends beyond tumor cells to various cells in the tumor microenvironment. Overall, GPCRs are central to many physiological functions and offer potential targets for therapeutic interventions.

GPCRs have substantial significance in pharmacology and serve as primary drug targets for therapeutic interventions. Approximately 30% of currently marketed drugs act on GPCRs, highlighting their pharmaceutical importance. By targeting specific GPCRs, drugs can modulate cellular signaling pathways and influence various physiological processes. GPCR-targeted drugs are used in diverse therapeutic areas, including cardiovascular diseases, respiratory disorders, neurological disorders, psychiatric conditions, and cancer. Understanding GPCR structure, ligand interactions, and signaling pathways has facilitated the development of drugs that specifically modulate GPCR activity. Additionally, ongoing research on GPCRs continues to uncover new potential targets for drug discovery.