G-protein-coupled receptors are biological transmembrane receptors that are essential for eukaryotes. They can recognize hormones such as adrenaline and histamine, but are also used for the recognition of taste, smell and light (vision). GPCR's are also essential within the brain as receptors for neurotransmitters. In the brain, GPCR's work alongside Ligand gated ion channels in the thought process, but the GPCR's can have a more permanent effect on the recieving cell and are thus also believed to play a role in memory. Once the receptor recognizes its specific signal, it activates a G protein within the cell as a first element in the internal singnal transduction chain.
G-protein-coupled receptors are proteins that posess seven transmembrane elements (parts that cross the plasma membrane), all of them α helices. The extracellular parts of the receptor can by glycosilated. These extracellular loops also contain highly conserved cysteine residues which build disulfide bonds to stabelize the receptor structure.
Ligand binding and signal transduction
In spite of most ligands binding at the extracellular domain to transmembrane receptors, small ligands of G-protein-coupled receptors can be recognized by the transmembrane domain. In these cases, the extracellular domain takes no part in the recognition.
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 so it gets highly affine to the ligand and activates the G protein, which then detatches from the receptor. The receptor can now either activate another G protein, or switch back to its inactive state.
G-protein-coupled receptors are known to react 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 :
- 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 rhodopsine in retina cells to compensate for exposure to bright light.