G protein-coupled receptors (GPCRs) are key communication devices, mediating signals between the cell’s exterior and interior. These receptors are widely distributed throughout the body and are involved in nearly all physiological processes. As the largest and most diverse group of membrane receptors in eukaryotes, GPCRs enable cells to perceive and respond to various signals.
Unpacking Their Structure
GPCRs are characterized by a distinct structure: a single polypeptide chain that threads back and forth across the cell membrane seven times. Each pass forms an alpha-helix, creating a bundle of seven transmembrane helices embedded within the lipid bilayer. This structure leads to their alternative name: “seven-transmembrane receptors” (7TM receptors).
The receptor has an extracellular domain, extending outside the cell, which binds incoming signals (ligands). An intracellular domain inside the cell interacts with G proteins. This arrangement allows GPCRs to receive external signals and transmit them inward, initiating cellular responses.
How They Transduce Signals
Signal transduction by GPCRs begins when a ligand binds to the receptor’s extracellular domain, causing a conformational change. This change enables the GPCR to activate an associated G protein, located on the inner surface of the cell membrane. G proteins are heterotrimeric, composed of three subunits: alpha ($\alpha$), beta ($\beta$), and gamma ($\gamma$).
In its inactive state, the G protein’s alpha subunit is bound to guanosine diphosphate (GDP). Upon GPCR activation, GDP on the alpha subunit is replaced by guanosine triphosphate (GTP). This exchange leads to the dissociation of the GTP-bound alpha subunit from the beta-gamma dimer.
Both the activated GTP-bound alpha subunit and the beta-gamma dimer then interact with various effector proteins, such as enzymes or ion channels, within the cell membrane or cytoplasm. For instance, activated Gαs subunits often stimulate adenylyl cyclase, an enzyme that converts ATP into cyclic AMP (cAMP). Conversely, Gαi subunits can inhibit adenylyl cyclase, leading to a decrease in cAMP levels.
Another common pathway involves Gαq family members, which activate phospholipase C (PLC). PLC then cleaves a membrane lipid called phosphatidylinositol bisphosphate (PIP2) into two second messengers: inositol triphosphate (IP3) and diacylglycerol (DAG). These “second messengers” amplify the signal throughout the cell, leading to responses like changes in gene expression, muscle contraction, or neurotransmitter release. Signal termination occurs when the GTP on the alpha subunit is hydrolyzed back to GDP, causing the G protein subunits to reassociate and return to their inactive state.
Their Diverse Physiological Roles
GPCRs are involved in an extensive array of physiological processes, demonstrating their importance in maintaining bodily functions. In sensory perception, GPCRs are fundamental to vision, where opsins translate light into cellular signals, and to taste, with receptors mediating responses to bitter, umami, and sweet substances. They also play a role in the sense of smell, as olfactory receptors bind to odorant molecules.
Beyond the senses, GPCRs regulate involuntary bodily functions, including the control of heart rate and blood pressure. They are also involved in immune responses and inflammation, responding to various chemical signals to coordinate the body’s defense mechanisms. Neurotransmission relies on GPCRs, with receptors in the brain binding to neurotransmitters like dopamine, serotonin, adrenaline, histamine, GABA, and glutamate, influencing mood and behavior.
GPCRs also regulate cellular metabolism, hormone secretion, and cell growth. Their ability to respond to diverse stimuli, from light and odors to hormones and neurotransmitters, highlights their role in orchestrating bodily functions and ensuring internal balance.
Targeting GPCRs in Medicine
The pervasive involvement of GPCRs in physiological processes makes them significant targets in medicine, particularly for drug development. An estimated 30% to 50% of all currently prescribed drugs exert their therapeutic effects by modulating the activity of GPCRs. This makes them the largest family of proteins targeted by approved drugs.
Drugs that target GPCRs are used to treat a wide range of diseases and conditions. For instance, antihistamines for allergies, bronchodilators for asthma, and angiotensin receptor blockers for hypertension all work by modulating specific GPCRs. In mental health, drugs used for depression and schizophrenia often target GPCRs that bind neurotransmitters. Pain management also involves drugs that interact with GPCRs, such as opioid receptors.
Therapeutic interventions often involve two main approaches: agonists and antagonists. Agonists are drugs that bind to and activate GPCRs, mimicking the action of the natural ligand to elicit a cellular response. Conversely, antagonists bind to GPCRs but block the binding of natural ligands, thereby preventing or reducing the receptor’s activation. The continued study of GPCRs, including orphan GPCRs (those whose natural ligands are not yet known), promises to uncover new targets for treating various pathologies.