G-protein-coupled receptors, or GPCRs, are a family of proteins found on the surface of cells. They act as cellular “antennas,” receiving signals from the outside environment and transmitting them into the cell’s interior. These receptors are fundamental to how cells communicate and respond to a vast array of external stimuli, ranging from light and odors to hormones and neurotransmitters. With hundreds of different types in the human body, GPCRs are involved in nearly every physiological process, underscoring their widespread importance.
Understanding Their Structure
A GPCR is a single polypeptide chain that threads through the cell’s plasma membrane seven times, earning them the nickname “seven-transmembrane (7-TM) receptors.” This structure forms a barrel-like shape within the membrane, featuring an extracellular region for ligand binding, seven alpha-helical transmembrane domains, and an intracellular C-terminus. The receptor’s intracellular portion interacts with an associated G-protein, a component of the signaling system.
The G-protein is a heterotrimeric complex, consisting of three subunits: alpha (α), beta (β), and gamma (γ). In its inactive state, a guanosine diphosphate (GDP) molecule is bound to the alpha subunit. Both the alpha and gamma subunits are anchored to the cell membrane by lipid tails, positioning the G-protein close to the GPCR for efficient interaction.
How They Transmit Signals
Signal transduction through GPCRs begins when a ligand binds to the extracellular portion of the receptor. This binding causes a conformational change in the GPCR’s structure. This change enables the activated GPCR to interact with the associated G-protein, promoting the exchange of GDP for guanosine triphosphate (GTP) on the G-protein’s alpha subunit.
Upon binding GTP, the alpha subunit dissociates from the beta-gamma complex. Both the GTP-bound alpha subunit and the beta-gamma complex become active and regulate downstream effector proteins. These effector proteins are enzymes, such as adenylyl cyclase or phospholipase C (PLC), or ion channels. For instance, activated adenylyl cyclase can catalyze the production of cyclic AMP (cAMP) from ATP, while activated PLC can cleave phosphoinositol bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These second messengers then diffuse within the cell to amplify and propagate the signal, leading to diverse cellular responses, often by activating specific protein kinases like protein kinase A (PKA) or protein kinase C (PKC).
Their Widespread Importance in the Body
In our senses, rhodopsin, a GPCR, is responsible for vision by detecting light. GPCRs in taste receptor cells allow us to perceive sweet, umami, and bitter tastes, while olfactory receptors, also GPCRs, enable our sense of smell.
Beyond sensory functions, GPCRs are involved in nervous system regulation, influencing mood, learning, memory, and pain perception through their interactions with neurotransmitters like serotonin, dopamine, and cannabinoids. In the cardiovascular system, adrenergic receptors, a type of GPCR, help regulate heart rate and blood pressure, responding to hormones like adrenaline. GPCRs are also involved in immune responses by binding inflammatory mediators and chemokines, and they are implicated in metabolic regulation and reproductive processes.
Targeting GPCRs in Medicine
The pervasive roles of GPCRs in the body make them important targets for pharmaceutical intervention. Around 30% to 50% of all currently marketed drugs exert their therapeutic effects by modulating GPCR activity.
Many common medications work by either activating (agonists) or blocking (antagonists) specific GPCRs. For instance, beta-blockers like propranolol target beta-adrenergic receptors to treat conditions such as hypertension and heart failure. Antihistamines, such as diphenhydramine, alleviate allergic reactions by blocking histamine receptors. Opioid analgesics, including morphine, manage pain by acting on opioid receptors. Ongoing research into GPCRs continues to inform the development of new, more targeted therapies for a wide range of diseases, including neurological disorders, metabolic conditions, and inflammatory diseases, aiming for improved efficacy and fewer side effects.