G-protein coupled receptors

G protein-coupled receptors, GPCRs for short, are a large family of transmembrane receptors that transmit signals to 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 play a role mainly as phytohormone receptors.

In humans, of the approximately 21 000 genes, about 1000 genes could be defined as GPCR genes. For about 140 GPCRs found, the endogenous ligands could not yet be identified (orphan receptors). The large number of receptors alone indicates the great physiological importance of GPC receptors.

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 leads to the isomerization of retinal, which is coupled to the GPC receptor rhodopsin, at the photoreceptors of the eye. About 300 different GPC receptors serve to perceive different odor nuances.

Allosteric ligands: Allosteric ligands bind to the receptor outside the actual ligand binding site and thus change its conformation. In doing so, the ligand binding site can be altered so 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 they express a co-receptor (chemokine receptors such as CXCR4 and CCR5). For example, the allosteric inhibitor maraviroc binds to CCR5, preventing the actual receptor from binding to viral proteins and thus preventing virus entry (entry inhibitor).

Bitopic ligands: This type of ligand binds to both the ligand binding site and 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 assemble into dimeric or oligomeric receptor complexes. The complexes may be composed of the same (homo(di)mere) or different receptor complexes (hetero(di)mere). Oligomeric receptor complexes have been detected, for example, in adrenergic receptors or dopamine receptors. The components may act as allosteric modulators and reciprocally influence their functions, such as ligand binding or activation of signal transduction chains.

GPCR and drugs: Only the identification of GPCR and their ligands allowed a targeted search for drugs targeting these receptors. Binding tests can be used to determine the influence of a test substance on the GPCR.

• An agonist binds with an identical effect as 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 eliciting an intracellular effect.
• A partial antagonist elicits an attenuated effect compared to the ligand.

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