In cell biology, G-protein-coupled receptors (also known as GPCRs, seven transmembrane receptors, heptahelical receptors, or 7TM receptors) are transmembrane receptors that transduce an extracellular signal (ligand binding) into an intracellular signal (G protein activation). The GPCR protein superfamily is the largest protein family known, members of which are involved in practically every intercellular biological process and bind as ligands practically every type of biological macromolecule. This pervasive presence and diversity is responsible for GPCRs being the target of 40 to 50% of modern medicinal drugs.^[1] Cell biology (also called cellular biology or cytology, from the Greek kytos, container) is an academic discipline which studies cells. ... Transmembrane receptors are integral membrane proteins, which reside and operate typically within a cells plasma membrane, but also in the membranes of some subcellular compartments and organelles. ... In biology, signal transduction is any process by which a cell converts one kind of signal or stimulus into another. ... G-proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. ...

Physiological roles

Examples of the physiological processes in which GPCRs participate 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 G-protein coupled receptor pathways. These systems are responsible for control of many automatic functions of the body such as blood pressure, heart rate and digestive processes.

A rhodopsin molecule in the cell membrane. ... A rhodopsin molecule (yellow) in the cell membrane (blue). ... The olfactory epithelium is a specialized epithelial tissue inside the nasal cavity that is involved in smell. ... Orders Subclass Monotremata Monotremata Subclass Marsupialia Didelphimorphia Paucituberculata Microbiotheria Dasyuromorphia Peramelemorphia Notoryctemorphia Diprotodontia Subclass Placentalia Xenarthra Dermoptera Desmostylia Scandentia Primates Rodentia Lagomorpha Insectivora Chiroptera Pholidota Carnivora Perissodactyla Artiodactyla Cetacea Afrosoricida Macroscelidea Tubulidentata Hyracoidea Proboscidea Sirenia The mammals are the class of vertebrate animals characterized by the presence of mammary glands... In the anatomy of animals, the brain, or encephalon, is the supervisory center of the nervous system. ... Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between two neurons: the presynaptic neuron and the postsynaptic neuron. ... Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ... The immune system is the organ system that protects an organism from outside biological influences. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... Chemokines are a class of chemotactic cytokines, or small secreted protein signals. ... Histamine is a biogenic amine chemical involved in local immune responses as well at regulating physiological function in the gut and acting as a neurotransmitter. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... The word sympathetic means different things in different contexts. ... Anatomy and Physiology of the A.N.S. In contrast to the voluntary nervous system, the involuntary or autonomic nervous system is responsible for homeostasis, maintaining a relatively constant internal environment by controlling such involuntary functions as digestion, respiration, and metabolism, and by modulating blood pressure. ...

Receptor structure

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 two 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 mammalian G protein-coupled receptor, 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 transmemebrane helix proteins (such as channelrhodopsin) that resemble G proteins may contain different functional groups, such as entire ion channels, within their protein. Integral membrane protein of the transmembrane type An Integral Membrane Protein (IMP) is a protein molecule (or assembly of proteins) that in most cases spans the biological membrane with which it is associated (especially the plasma membrane) or which, in any case, is sufficiently embedded in the membrane to remain... Within an integral membrane protein, a transmembrane helix is a segment that is alpha-helical in structure, roughly 20 amino acids in length and (though it may be presumed to lie within the protein, out of contact with the surrounding lipid bilayer) is said to span the membrane. ... Glycosylation is the addition of polysaccharides to molecules such as proteins. ... Cysteine is a naturally occurring hydrophobic amino acid which has a sulfhydryl group and is found in most proteins, however only in small quantities. ... A disulfide bond (SS-bond), also called a disulfide bridge, is a strong covalent bond between two sulfhydryl groups. ... Bacteriorhodopsin is a photosynthetic pigment used by archaea, most notably halobacteria. ... X-ray crystallography is a technique in crystallography in which the pattern produced by the diffraction of x-rays through the closely spaced lattice of atoms in a crystal is recorded and then analyzed to reveal the nature of that lattice. ... A rhodopsin molecule (yellow) in the cell membrane (blue). ... Channelrhodopsin-2 (ChR2) is an ion channel that is directly opened by light. ...

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. In chemistry, a ligand is an atom, ion or functional group that is bonded to one or more central atoms or ions, usually metals generally through co-ordinate covalent bond. ...

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. In biology, signal transduction is any process by which a cell converts one kind of signal or stimulus into another. ... G-proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. ... In chemistry, a chemical conformation is the spatial arrangement of atoms in a molecule. ...

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-proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. ...

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 is the addition of a phosphate (PO4) group to a protein or a small molecule. ... Cytoplasm is the colloidal, semi-fluid matter contained within the cells plasma membrane, in which organelles are suspended. ... A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). ...

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. In cell biology, cAMP-dependent protein kinase (cAPK), also known as protein kinase A (PKA, EC 2. ... Adenylate cyclase (EC 4. ... Structure of cAMP Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3-5-cyclic adenosine monophosphate) is a molecule that is important in many biological processes; it is derived from adenosine triphosphate (ATP). ...

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. 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.

A rhodopsin molecule (yellow) in the cell membrane (blue). ... Human eye cross-sectional view. ...

Receptor oligomerization

It is generally accepted that that G-protein-coupled receptors can form homo- and/or hetero-dimers and possibly more complex oligomeric structures. However, it is presently unclear what the functional significance of oligomerization is. This is an actively studied area in GPCR research.

References

1. ^  Filmore, David. (2004). It's a GPCR world. Modern Drug Discovery, 7(11). Retrieved 2005-02-04.