How do GPCRs work

G protein coupled receptor

Abbreviation: GPCR
English: G protein-coupled receptor

1 definition

G protein coupled receptors, short GPCR, are a class of receptors that trigger a cellular signal cascade via G-proteins (GTP-binding proteins). The G-protein-coupled receptors form the largest protein superfamily with more than 1,000 different members.

2 structure

The seven transmembrane domains that are always present are characteristic of G-protein-coupled receptors. A transmembrane domain consists of about 20 amino acids, each arranged in an α-helix. For this reason, GPCR are also largely synonymous with heptahelical receptors. The N-terminus of the protein is on the extracellular side, the C-terminus is intracellular.

3 classification

Based on their sequence homology and functional similarity, the G-protein-coupled receptors are divided into 6 classes:

Alternatively, G-protein-coupled receptors can be classified into:

  • Gs-coupled receptors that trigger a stimulating cascade
  • Gi-coupled receptors that trigger an inhibiting cascade
  • Gq-coupled receptors that activate protein kinase C via the second messenger pathway (mediated by phospholipase C) via IP3 and DAG
  • Gt-coupled receptors that activate c-GMP-dependent phosphodiesterase in rod cells via the alpha-t subunit of the G protein called transducin.
  • Golf-coupled receptors are found in the secondary sensory cells of the olfactory mucosa and serve the olfactory signaling pathway.
  • Ggust-coupled receptors are involved in the signaling pathways of the taste qualities sweet, umami and bitter. This large class is also called the T-receptor family ("T" for button) and further subdivided into T1 and T2 receptors.

4 examples

4.1 Glucagon receptor

An example of a G protein-coupled receptor is the glucagon receptor. The glucagon receptor is a membrane-bound 62 kDa protein that transmits its signal via G proteins and the effector adenylate cyclase.

If the hormone glucagon binds to the receptor, the exchange of GDP to GTP is promoted at the G protein. However, there is no phosphorylation of GDP in this process. GDP is only exchanged for GTP. After GTP binds to the G protein, it splits into the active α subunit and the inactive β / γ subunit.

The α-subunit migrates towards adenylate cyclase and activates it. This now promotes the rearrangement of ATP to cAMP, the so-called "hunger signal" of the cell. cAMP now continues the signal cascade and activates various kinases such as protein kinase A (PK-A), which in turn phosphorylates other enzymes of the cell metabolism and thus regulates it.

4.2 Smooth muscle contraction

4.2.1 Regulation on the myosin

The activation of phospholipase C via the alpha subunit of the G protein, which is anchored to the cytosolic side of the plasma membrane via a lipid tail, leads to the formation of the second messenger IP3 (inositol-1,4,5-triphosphate) and DAG (diacylglycerol ) from the phospholipid PIP2 (phosphatidylinositol-4,5-bisphosphate). IP3 induces the intracellular release of Ca2+. Approx2+ now binds to the calmodulin of the smooth muscle cells and leads to their conformation and activity change. The resulting approx2+-Calmodulin complex triggers the activity of myosin light chain kinase (MLCK), which then catalyzes the phosphorylation of the regulatory light chain of myosin. In this way, the myosin of the smooth muscle cell is activated via the IP3 signal transduction.

4.2.2 Regulation on actin

The approx2+-Calmodulin complex also leads to the activation of caldesmon, which subsequently separates from the actin-tropomyosin complex. This exposes the myosin binding site on the actin and initiates the contraction of the muscle cell.

4.3 Muscarinic acetylcholine receptor

Another example of a G protein-coupled receptor is the muscarinic acetylcholine receptor of the heart muscle cells (M2-Receptor). Acetylcholine is released when the parasympathetic system is activated, which causes the heart to slow down. Acetylcholine binds to the G-protein-coupled receptor and, as a result of its conformational change, activates the beta-gamma complex of the Gi protein. This complex opens the potassium channels and K.+-Ions flow into the extracellular space.

4.4 Further examples

5 Clinical Significance

A large number of drugs work by interacting with G-protein-coupled receptors. These include, for example, beta blockers and a subgroup of platelet aggregation inhibitors.

Autoantibodies against G-protein-coupled receptors can cause various clinical pictures, for example dilated cardiomyopathies.

6 literature