G protein-coupled receptor

In cell biology, a G-protein-coupled receptor is one of a class of integral membrane proteins belonging to the "7TM" superfamily of transmembrane receptors, examples being 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.

Receptor structure

Like all so-called 7TM receptors, G-protein-coupled receptors 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.

Receptor regulation

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 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.

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 :

1. 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.
2. 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.