G-protein coupled receptors (GPCRs)

GPCR

G-protein-coupled receptors (GPCR) are membrane receptors. They can be found mainly on cell surface but also organelles surfaces and represents the largest family of membrane receptors. They play a significant role in the core cell signaling pathways. Thus, GPCRs are often involved in diseases making them interesting targets for therapeutic treatment of cancer, inflammatory, cardiac and metabolic disorders for example. Proteogenix, in its will to help researchers in the fight against diseases and to support global health, has developed GPCR related proteins of high quality.

GPCR Structure

GPCR proteins have 7 transmembrane alpha-helixes arranged as a barrel which is the reason why they are also called seven (pass)-transmembrane domain receptors. The N-terminus is outside of the cell whereas the C-terminus is in the inside bearing amphipathic helixes. The C-Terminus binds to the heterotrimeric G protein which is critical in GPCR signaling cascade.

GPCR Signalling

The GPCR signaling cascade is induced by a wide range of stimuli such as neurotransmitters, hormones, odorants, ions or even photons depending on the receptor. A signal molecule bounds in the external N-Terminus and induces a conformational change. The GPCR is now able to interact with the near G protein. This last protein consists in G alpha, G beta and G gamma subunitss. GDP molecules are bound to the G alpha subunit that is activated when it interacts with the GPCR. It triggers the exchange between GTP from the GDP molecule. The G protein further dissociates in Gα-GTP and Gβγ complexes. Gα-GTP will act on enzymes whereas Gβγ heterodimer usually interact with ion channels pathways. Gα hydrolyses the GTP and G subunits can gather again to form the G protein and begin another signal cascade. This signaling is often regulated by feedback pathways induced with the G protein downward cascade.

G proteins

There are 4 types of G proteins involved in different cascades. They are named after the activity of the Gα subunit. Stimulatory Gα (Gαs) stimulates adenylyl cyclase which in turn generates cyclic AMP (cAMP). This will modulate the activity of ion channels PKA activity. Inhibitory Gα (Gαi) play a role in the same pathways having an inhibitory effect on adenylyl cyclases. Gαq has a stimulatory activity on PLCβ which cleaves PIP2 into IP3 and DAG. IP3 is responsible for calcium ion levels in the cells. Transducing Gα (Gαt) is involved in the cGMP deactivation.

GPCR interest

Thanks to the size of its superfamily GPCR are interesting as studies target. They are critical for many Cell signaling pathways and produce many second messengers. A GPCR can trigger the same pathway as long as its stimulatory ligand is bound to it. Therefore a strong signal can originate from a single stimulus. This is also one interest of these receptors for therapeutic purposes: low level of drugs targeting GPCRs would be necessary to create an important signal.