G-protein coupled receptors

G protein-coupled receptors (GPCR) are a large family of transmembrane receptors that transmit signals into the interior of a cell via G proteins (GTP-binding proteins) (see also signal transduction).

G-protein-coupled receptors are found in almost all living organisms, including vertebrates, invertebrates, protozoa and fungi. Some plant cell membrane proteins can also activate heterotrimeric G-proteins. They mainly play a role as phytohormone receptors.

In humans, around 1000 of the approximately 21,000 genes have been defined as GPCR genes. The endogenous ligands of around 140 GPCRs have not yet been identified (orphan receptors). The high number of receptors alone indicates the great physiological importance of GPCRs.

G-protein coupled receptors can be divided into:

• Gs-coupled receptors("s" for stimulating), which trigger a stimulatory cascade
• Gi-coupled receptors("i" for inhibitory) that trigger an inhibitory cascade
• Gq-coupled receptors that activate phospholipase C via the Second Messenger Pathway
• Gt-coupled receptors that activate the c-GMP-dependent phosphodiesterase in the rod cells of the eye via the alpha-t subunit of the G protein (also called transducin).

G-protein-coupled receptors are characterized by common molecular structures. Always present are 7 transmembrane domains (syn.: heptahelical receptors) consisting of about 20 amino acids. These are arranged in an alpha helix structure. The N-terminal of the receptor protein is located extracellularly, the C-terminal intracellularly. This formation ensures transmembrane signal transmission.

As the receptor protein crosses the cell membrane several times, extracellular and intracellular loops are formed (see Fig.). Together with the amino terminus, the extracellular loops form the extracellular domain involved in ligand binding. The carboxyl terminus, together with the intracellular loops, is responsible for contact with intracellular signaling molecules. Binding of the extracellular portion of the G receptor to its ligand, changes its spatial protein information (conformation). The altered conformation is sensed by intracellular molecules. Thus, the signal has arrived in the cell and can be further processed intracellularly via contact with G proteins. The G proteins consist of three subunits (alpha, beta, gamma).

In the inactive state of the receptor, guanosine diphosphate (GDP) is bound. When the GPC receptor is activated by the binding of the ligand, GDP is exchanged for guanosine triphosphate (GTP). In the wake of this exchange, the alpha subunit dissociates from the ligand-receptor complex with the bound GTP.

Both subunits (both the alpha subunit with GTP and the beta/gamma subunit) can, independently, process downstream signal transduction pathways.

Previously, it was assumed that after binding a ligand, a GPCR adopts a well-defined active conformation that activates all downstream signal transduction pathways (G-proteins, beta-arrestin). Thus, different drug action profiles were erroneously attributed to different affinities for the receptors and to different signal strengths. In the meantime, however, it has been demonstrated that a GPCR can adopt different active conformations depending on the bound ligand, which selectively initiate different signal transduction chains.

GPC receptors are not only activated by endogenous ligands, but also by external physical stimuli. For example, the incidence of light on the photoreceptors of the eye leads to the isomerization of retinal, which is coupled to the GPC receptor rhodopsin.

In the olfactory system, around 300 different GPC receptors are used to perceive different odor nuances.

Allosteric ligands: Allosteric ligands bind to the receptor outside the actual ligand binding site and thus change its conformation. The ligand binding site can be changed in such a way that the actual ligands bind better or worse. For example, the human immunodeficiency virus (HIV) binds to the surface molecule CD4 (on T helper cells and macrophages). However, the virus can only enter the cell if it expresses a co-receptor (chemokine receptors such as CXCR4 and CCR5). For example, the allosteric inhibitor maraviroc binds to CCR5 and thus prevents the actual receptor from binding to viral proteins, thereby preventing the virus from entering the cell (entry inhibitor).

Bitopic ligands: This type of ligand binds both to the ligand binding site and to allosteric binding sites of the receptor. Therapeutically, this type of ligand can be used to further increase the affinity and selectivity of a drug for the target receptor.

GPCR complexes: GPCRs can combine to form dimeric or oligomeric receptor complexes. The complexes can be composed of the same (homo(di)mere) or different (hetero(di)mere) receptor complexes. Oligomeric receptor complexes have been detected, for example, in adrenergic receptors or dopamine receptors. The components can act as allosteric modulators and mutually influence their functions, such as ligand binding or the activation of signal transduction chains.

GPCRs and drugs: Only the identification of GPCRs and their ligands allowed a targeted search for drugs that act on these receptors. Binding tests can be used to determine what effect a test substance has on the GPCR.

• An agonist binds with an identical effect to the actual ligand.
• An inverse agonist inhibits the ligand-independent basic activity of the GPCR.
• An antagonist prevents the ligand from binding to the receptor without itself triggering an intracellular effect.
• A partial antagonist produces a weakened effect compared to the ligand.

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