In cell biology,
G-protein-coupled receptors are a class of proteins that includes members of the "7TM" superfamily of
transmembrane receptors, examples being the receptors of the olfactory sensory 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 of the 7TM type are
integral membrane proteins that possess seven membrane-spanning elements or
transmembrane helices. The extracellular parts of the receptor can by
glycosylated[?]. These extracellular loops also contain highly conserved
cysteine residues which build
disulfide bonds to stabilize the receptor structure. Detailed structural information for most of these receptors is based on analogy
bacteriorhodopsin[?], a member of the 7TM class whose structure has been determined by both electron and
X ray-based crystallography
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 detatches 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.
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.
cAMP-dependent protein kinases (for example,
proteine kinase A[?]) are activated by the signal chain coming from the G protein (that was activated by the receptor) via
adenylate cyclase A[?] and
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.
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.
- Arrestine[?] linking. The phosphorylated receptor can be linked to arrestine 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.