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G protein-coupled receptors (GPCRs), also known as seven transmembrane receptors, heptahelical receptors, or 7TM receptors, are a protein family of transmembrane receptors that transduce an extracellular signal (ligand binding) into an intracellular signal (G protein activation). The GPCRs are the largest protein family known, members of which are involved in all types of stimulus-response pathways, from intercellular communication to physiological senses. The diversity of functions is matched by the wide range of ligands recognized by members of the family, from photons (rhodopsin, the archetypal GPCR) to small molecules (in the case of the histamine receptors) to proteins (for example, [Chemokines? chemokine receptors]). This pervasive involvement in normal biological processes has the consequence of involving GPCRs in many pathological conditions, which has led to GPCRs being the target of 40 to 50% of modern medicinal drugs.

The seven transmembrane α-helix structure of a G protein-coupled receptor.

Physiological roles

GPCRs are present in a wide variety of physiological processes. Some examples include:

  1. The visual sense: the opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose.
  2. The sense of smell: receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
  3. Behavioral and mood regulation: receptors in the mammalian brain bind several different neurotransmitters, including serotonin and dopamine
  4. Regulation of immune system activity and inflammation: chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response
  5. Autonomic nervous system transmission: both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways. These systems are responsible for control of many automatic functions of the body such as blood pressure, heart rate and digestive processes.

There are two types of GPCRs, viz chemosensory (type A, eg rhodopsins)and endo (type B, eg glucagon) GPCRs.

Receptor structure

GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices (Figure 1). The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues which build disulfide bonds to stabilize the receptor structure.

Early structural models for GPCRs were based on their weak analogy to bacteriorhodopsin for which a structure had been determined by both electron and X ray-based crystallography. In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin, was solved. While the main feature, the seven transmembrane helices, is conserved, the structure differs significantly from that of bacteriorhodopsin. Some seven transmembrane helix proteins (such as channelrhodopsin) that resemble GPCRs may contain different functional groups, such as entire ion channels, within their protein.

Ligand binding and signal transduction

Sequence of events after activation of a G protein-coupled receptor (red) by a hormone (orange). See the main text for details.

While in other types of receptors that have been studied ligands bind externally to the membrane, the ligands of GPCRs 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 is an overly simplistic explanation, but suffices to convey the overall set of events.

It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states.[2] The binding of ligands to the receptor may shift the equilibrium (for example see link). 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. Activated G proteins are bound to GTP.

The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state.

GPCR signaling without G proteins

In the late 1990s, evidence began accumulating that some GPCRs are able to signal without G proteins. The ERK2 mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the slime mold D. discoideum despite the absence of the associated G protein α- and β-subunits.

In mammalian cells the well-studied β2-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G protein mediated signalling. It therefore seems likely that some mechanisms previously believed to be purely related to receptor desensitisation are actually examples of receptors switching their signalling pathway rather than simply being switched off.

Receptor regulation

GPCRs become desensitized when exposed to their ligand for a prolongued period of time. There are two recognized forms of desensitization: 1) homologus desensitization, in which the activated GCPR is downregulated and 2) heterologus desensitization, where the activated GCPR causes downregulation of a different GCPR. 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 (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 GPCRs.

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. 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.

Receptor oligomerization

It is generally accepted that G protein-coupled receptors can form homo- and/or hetero-dimers and possibly more complex oligomeric structures. However, it is presently unproven that true hetero-dimers exist. Present bio-chemical and physical techniques lack the resolution to differentiate between distinct homo-dimers assembled into an oligomer or true 1:1 hetero-dimers. It is also unclear what the functional significance of oligomerization is. This is an actively studied area in GPCR research.

It is generally accepted that G protein-coupled receptors can form homo- and/or heterodimers and possibly more complex oligomeric structures, and indeed heterodimerization has been shown to be essential for the function of receptors such as the metabotropic GABA(B) receptors. Present bio-chemical and physical techniques lack the resolution to differentiate between distinct homo-dimers assembled into an oligomer or true 1:1 hetero-dimers. It is also unclear what the functional significance of oligomerization might be, although it is thought that the phenomenon may contribute to the pharmacological heterogeneity of GPCRs in a manner not previously anticipated. This is an actively studied area in GPCR research.





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