In cell biology, G-protein-coupled receptors, also known as GPCR, seven transmembrane receptors, heptahelical receptors, or 7TM receptors, are a class of transmembrane receptors. Examples are the receptors of the olfactory epithelium that bind odorants and receptors of the neurotransmitter serotonin in the mammalian brain. Upon ligand binding, these receptors activate G proteins.
G protein-coupled receptors are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain highly conserved cysteine residues which build disulfide bonds to stabilize the receptor structure. Early structural models for G protein coupled receptors were based on their weak analogy to bacteriorhodopsin for that a structure had been determined by both electron and X ray-based crystallography. In 2000, the first crystal structure of a G protein-coupled receptor, that of rhodopsin, was solved. While the main feature, the seven transmembrane helices, is conserved, the structure differs significantly from that of bacteriorhodopsin.
Ligand binding and signal transduction
While in other types of receptors that have been studied ligands bind externally to the membrane, the ligands of G-protein-coupled receptors typically bind within the transmembrane domain.
The transduction of the signal through the membrane by the receptor is not completely understood. It is known that the inactive G protein is bound to the receptor in its inactive state. Once the ligand is recognized, the receptor shifts conformation and thus mechanically activates the G protein, which detaches from the receptor. The receptor can now either activate another G protein, or switch back to its inactive state. This model is rather simplified. Please read the discussion of this page for a brief summary of the present model.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of ligands to the receptor may shift the equilibrium. Three types of ligands exist: agonists are ligands which shift the equilibrium in favour of active states; inverse agonists are ligands which shift the equilibrium in favour of inactive states; and neutral antagonists are ligands which do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.
If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G-proteins are actually pre-coupled. For example, binding of G-proteins to receptors affects the receptor's affinity for ligands.
G-protein-coupled receptors are known to become less sensitive to their ligand when they are exposed to it for a prolonged period of time. The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases.
Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (also known as Protein Kinase A) are activated by the signal chain coming from the G protein (that was activated by the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active, the more kinases are activated, the more receptors are phosphorylated.
Phosphorylation by GRKs
The G-protein-coupled Receptor Kinases (GRKs) are protein kinases that phosphorylate only active G-protein-coupled receptors.
Phosphorylation of the receptor can have two consequences :
- Translocation. The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone.
- Arrestin linking. The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, effectively switching it off for a short period of time. This mechanism is used, for example, with rhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin binding to the receptor is a prerequisite for translocation.
It is generally accepted that that G-protein-coupled receptors can form homo- and/or hetero-dimers and possibly more complex oligomeric structures2. However, it is presently unclear what the functional significance of oligomerization is. This is an actively studied area in GPCR research.
GPCRs and Health Care
It is generally accepted that a major percentage, somewhere in the 40% to 50% range, of pharmaceuticals target GPCRs1.
Note 1: Filmore, David. (2004). It's a GPCR world (http://pubs.acs.org/subscribe/journals/mdd/v07/i11/html/1104feature_filmore.html). Modern Drug Discovery, 7(11). Retrieved 2005-02-04.