G protein-coupled receptors (GPCRs) represent the largest and most diverse family of cell surface receptors in the human body. These specialized proteins sit within the cell membrane, acting as molecular receivers for external signals. By responding to stimuli like light, odorants, hormones, and neurotransmitters, GPCRs translate messages from outside the cell into a specific internal response. Understanding their organization and categorization is fundamental to grasping their wide-ranging role in human physiology and their importance in modern medicine.
Defining GPCR Classification Systems
The vast GPCR superfamily, which includes approximately 800 members in the human genome, is primarily organized using a system based on sequence homology—the similarity in the amino acid structure of the receptor proteins. This phylogenetic approach is the foundation for the most commonly used framework, which divides GPCRs into six main classes, labeled A through F.
The classification system is sometimes referred to by the acronym GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin receptor families). Class A, or the Rhodopsin-like family, is the largest, encompassing hundreds of receptors that respond to small molecules, peptides, and light. The six main classes are:
- Class A (Rhodopsin-like)
- Class B (Secretin-like)
- Class C (Metabotropic Glutamate and \(\text{GABA}_{\text{B}}\) receptors)
- Class D (Fungal Mating Pheromone receptors)
- Class E (cAMP receptors)
- Class F (Frizzled/Smoothened receptors)
This organization helps predict a receptor’s likely function and its potential interaction with other cellular components.
Structural and Functional Features of Major Classes
The major GPCR classes are distinguished by structural hallmarks, particularly in the regions that interact with ligands and G proteins. Class A, the Rhodopsin-like family, is characterized by a short extracellular N-terminus and a conserved amino acid sequence motif, the DRY sequence, found on the third intracellular loop. Its ligand-binding pocket is formed within the core of the seven transmembrane helices, allowing it to bind small ligands like adrenaline or acetylcholine.
In contrast, Class B, or the Secretin-like family, features a larger extracellular N-terminal domain. This domain is necessary for binding their ligands, which are larger peptide hormones such as glucagon and secretin. The binding site for these larger molecules is located far from the cell membrane, unlike the deep pocket binding seen in Class A receptors.
Class C, which includes metabotropic glutamate receptors and \(\text{GABA}_{\text{B}}\) receptors, is structurally unique due to its large, multi-domain extracellular region. This domain, sometimes called a “venus flytrap” domain, binds amino acid ligands like glutamate. Class C receptors generally function as dimers, meaning two receptor units must associate to form a functional complex, a requirement not shared by most Class A receptors.
The Signal Transduction Mechanism
Despite their structural diversity, all GPCR classes share a common mechanism for transmitting a signal across the cell membrane. The process begins when a ligand binds to the receptor, causing a conformational shift that exposes a binding site on the intracellular side for an inactive heterotrimeric G-protein (composed of alpha (\(\alpha\)), beta (\(\beta\)), and gamma (\(\gamma\)) subunits).
The binding of the activated receptor causes the G-protein to release guanosine diphosphate (GDP) from its alpha subunit and immediately bind guanosine triphosphate (GTP). This exchange causes the G-protein complex to dissociate, splitting into an active \(\text{G}\alpha\)-GTP subunit and a \(\text{G}\beta\gamma\) dimer.
These active subunits move along the inner surface of the cell membrane to engage various effector proteins. For example, the \(\text{G}\alpha\) subunit may activate adenylyl cyclase, which generates the second messenger cyclic AMP (cAMP), or it may activate phospholipase C. Both the \(\text{G}\alpha\) subunit and the \(\text{G}\beta\gamma\) dimer regulate multiple downstream pathways, amplifying the original signal. The signal is terminated when the \(\text{G}\alpha\) subunit hydrolyzes the bound GTP back into GDP, causing the subunits to reassociate into an inactive heterotrimeric complex, ready for the next cycle.
Therapeutic Targeting and GPCR Classes
The understanding of GPCR classification holds practical implications for drug development and pharmacology. Knowing the target receptor’s specific class helps researchers predict the likely location of the ligand-binding pocket, the types of molecules that might bind, and the downstream signaling pathways that will be affected. This knowledge reduces the time and cost associated with identifying new therapeutic compounds.
GPCRs represent the largest family of targets for approved medications, with roughly 30% to 36% of all FDA-approved drugs acting on them. Medications targeting GPCRs manage a wide range of conditions, including hypertension, allergies, pain, and metabolic disorders. The structural differences between classes, such as the large extracellular domains in Class B and C, provide unique opportunities for drug design not possible with Class A receptors.