G-proteins are a family of proteins that function as molecular switches, transmitting signals from outside a cell to its interior. G-proteins are widespread throughout the body and are involved in numerous processes, from our sense of sight to how we react to hormones.
How a G-Protein Becomes Active
A G-protein exists in an inactive state when bound to guanosine diphosphate (GDP). The protein is a heterotrimer, composed of three different subunits: alpha (α), beta (β), and gamma (γ). In its inactive form, the G-protein, with GDP attached to the alpha subunit, is associated with a G-protein coupled receptor (GPCR) on the inner surface of the cell membrane.
The activation process begins when a molecule, such as a hormone or neurotransmitter, binds to the outside of a GPCR, causing the receptor to change shape. This change is transmitted to the G-protein, prompting the alpha subunit to release GDP and exchange it for a molecule of guanosine triphosphate (GTP). The cell maintains a high concentration of GTP relative to GDP, ensuring this exchange happens efficiently.
Once GTP is bound, the G-protein is considered active. This binding triggers the GTP-bound alpha subunit to detach from both the GPCR and the beta-gamma subunit complex. The separated alpha subunit and the beta-gamma complex are then free to interact with other molecules inside the cell, initiating a cascade of signaling events. This activation cycle can be repeated as long as the initial signal molecule remains bound to the GPCR, allowing for signal amplification.
The Role of Active G-Proteins in the Body
Once activated, the dissociated G-protein subunits interact with their specific targets, known as effector proteins. The alpha subunit and the beta-gamma complex can regulate different effector proteins, including enzymes and ion channels. This allows for a diverse range of cellular responses from a single activation event.
A clear example of this process is the sense of smell. When an odor molecule binds to a GPCR in a sensory cell in your nose, it activates a G-protein. The activated alpha subunit then stimulates an enzyme called adenylyl cyclase. This enzyme converts ATP into cyclic AMP (cAMP), a second messenger that opens ion channels, generating a nerve impulse that your brain interprets as a specific scent.
The hormone adrenaline (epinephrine) also uses G-proteins. When adrenaline binds to GPCRs on heart muscle cells, it activates G-proteins that stimulate cAMP production. This increase in cAMP leads to a series of events that result in an increased heart rate and contractility, preparing the body for a “fight or flight” response.
G-Proteins in Health and Medicine
The proper functioning of G-protein signaling is important for health, and malfunctions are implicated in many diseases. Mutations that permanently alter the activation or inactivation of these pathways can lead to conditions like cardiovascular disorders, certain cancers, and endocrine problems. For instance, the toxin from the cholera bacterium locks a G-protein in its “on” state in intestinal cells, leading to a massive loss of fluids and severe diarrhea.
Because G-proteins are activated by GPCRs, these receptors are major targets for drug development. An estimated 30-35% of all drugs approved by the Food and Drug Administration (FDA) work by targeting GPCRs. These medications are designed to either mimic the natural signaling molecule to promote G-protein activation or to block the receptor to prevent it.
For example, beta-blockers are a class of drugs for heart conditions that work by blocking GPCRs that would normally be stimulated by adrenaline. This action prevents G-protein activation and slows the heart rate. The extensive role of G-proteins in cellular signaling makes them a continuing focus for discovering new therapies.