Site Loader
Rock Street, San Francisco

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; text-align: center; font: 11.0px Helvetica; min-height: 13.0px}
p.p2 {margin: 0.0px 0.0px 0.0px 0.0px; text-align: center; font: 11.0px Helvetica}
p.p3 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Helvetica}
p.p4 {margin: 0.0px 0.0px 0.0px 0.0px; text-align: center; font: 10.0px Helvetica}
p.p5 {margin: 0.0px 0.0px 0.0px 0.0px; text-align: center; font: 10.0px Helvetica; min-height: 12.0px}
p.p6 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Helvetica; min-height: 13.0px}
span.s1 {text-decoration: underline ; letter-spacing: 0.0px}
span.s2 {letter-spacing: 0.0px}
span.s3 {font: 7.3px Helvetica; letter-spacing: 0.0px}
span.Apple-tab-span {white-space:pre}

Describe the signalling pathways downstream of the heterotrimeric G proteins Gs, Gi and Gq

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

Heterotrimeric G proteins are made of three subunits, ?, ?, and ?, and are guanine nucleotide binding proteins as they bind to either guanosine diphosphate (GDP), if the protein is inactive, or guanosine triphosphate (GTP), if the protein is active. In its inactive state, the G protein is bound to a molecule of GDP. The binding of an agonist to a G protein coupled receptor (GPCR) causes a conformational change, and the G protein can bind to the GPCR. The molecule of GDP is then replaced with a molecule of GTP at the ? subunit, which detaches from the ? and ? subunits, which then form a beta-gamma dimer. The ? subunit then binds to a downstream effector, causing a response. The GTP molecule is then hydrolysed back into GDP, and the ? subunit can no longer bind to the effector and detaches. This causes the three subunits to reform once again to form the heterotrimeric G protein. This mechanism is shown in Figure 1.

Figure 1

G proteins function as molecular switches as they are turned on and off by the binding of an agonist to the GPCR. Therefore, they are able to transduce signals in the cell, which is involved in responding physiologically to hormones and neurotransmitters. More than 50% of drugs target GPCR.

Three classes of the G? subunit include the Gs, Gi and Gq. The Gs protein is involved in the activation of adenyl cyclase and therefore the production of cAMP. This is described in the second messenger model, which is as follows: Adrenaline binds to a receptor on a cell surface membrane, causing a conformational change of the Gs protein inside the cell. The GPCR in this mechanism is the ?-1 adrenergic receptor (?1-AR), which mainly binds to the Gs protein with the GDP attached. Glucagon and epinephrine bind to different GPCRs, but both produce the same 
outcome. Once again, the binding of the GTP causes the G? subunit to bind to and activate adenyl cyclase, which is an enzyme that converts ATP to cyclic AMP (cAMP). The activation of adenyl cyclase is brief as GTP is quickly hydrolysed back into GDP, but the short amount of time is sufficient for the signal to be transmitted from the conformational change of the receptor. At high concentrations, cAMP acts as a second messenger and binds to cAMP-dependent protein kinase A (PKA), activating it. This leads to the conversion of glycogen to glucose and the phosphorylation of proteins in muscle contraction. The use of this process in regulating blood sugar concentration is imperative in sustaining the body with sufficient glucose in order for rapid aerobic respiration to occur, especially during rigorous exercise, to produce ATP for muscle contraction. In addition, cAMP itself plays a part in nerve transmission, sensory input and hormones. Furthermore, the concentration of cAMP is directly proportional to the concentration of activated Gs. 

The Gs protein can also play a part in relaxation of airway smooth muscle, when involving the ?-2 adrenergic receptor. This is used commonly in the treatment of asthma through the inhalation of beta-agonists used to bind to the GPCR. In this, the protein kinase A produced phosphorylates myosin light-chain kinase, causing the smooth muscle relaxation. 

The cholera toxin is a protein produced by the bacterium Vibrio cholerae, and the disease cholera is caused by the disfunction of the Gs protein. This occurs when the ? subunit of the cholera toxin enters the plasma membrane and into the cytosol and causes permanent activation of the Gs protein by an ADP-ribosylation reaction. As a result, GTP is unable to hydrolyse back into GDP and adenyl cyclase is perpetually activated, producing large amounts of cAMP. This leads to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and the large outflow of water from the blood into the intestinal lumen. This leads to severe dehydration and diarrhoea. The effect of cholera on the Gs protein is shown in Figure 2.

Figure 2

In contrast, the Gi subunit is an inhibitor of adenyl cyclase and so prevents the production of cAMP from ATP. Of all the G protein types, Gi is expressed the most in most cell types. There are three types of Gi proteins – Gi-1, Gi-2, and Gi-3 – that are coded for by different genes. The inhibition of adenyl cyclase is thought to be due to the difference in binding region between Gi and Gs. In Gs, two regions of the protein are in contact with adenyl cyclase when it is bound: the switch II helix and the ?3-?5 loop. However, in Gi, it is suggested that it is the ?4-?6 loop interacts with a different surface of the adenyl cyclase instead to cause inhibition. 

In addition, the Gi protein is involved in certain functional events in muscle, such as actin filament polymerisation and contractile sensitisation. This is due to the activation of Rho through Rho guanine nucleotide exchange factors (GEFs). It is not known if this is due to the ? subunit or the ?? subunit, but it is worth stating that in Gi proteins, both the ? and ?? subunits are capable of modulating signals. The mechanisms for these events are not well-established, but from Figure 3, it is also known that the Gi protein has a role in promoting the growth of airway smooth muscle. 

Figure 3

In immunity, sphingosine-1-phosphate (S1P), a lipid mediator, assists in the movement of lymphocytes into the bloodstream from lymphoid organs via Gi coupled receptors. Additionally, in diseases such as asthma, chemokines that are released by bronchial epithelial cells in the lungs and mast cells recruit leukocytes such as neutrophils and eosinophils. The chemotaxis created by the chemokines released can be attenuated by pertussis toxin (PTX), which catalyses the ADP-ribosylation of the Gi protein. This causes the Gi protein to be unable to bind to the GPCR, and therefore remains in its inactive state bound to GDP. Hence, cAMP production cannot be inhibited as there is constant activation of adenyl cyclase. High concentrations of cAMP affects signalling and can cause an increase in the production of the hormone insulin, which leads to hypoglycaemia. 

Moreover, the activation of the Gi proteins from the coupling of chemokine receptors is required for chemotaxis in T cells (which involves migration of lymphocytes into the lymph nodes and lymphoid organs). As stated above, PTX is able to inactivate the Gi proteins, and in T cells that do not have Gi protein, there is a higher level of proinflammatory cytokines in the gut. This is related to inflammatory colitis, but it is not known if there is a direct correlation with the Gi protein.

The last class of the three G? proteins is the Gq protein. Gq’s main function is to activate phospholipase C (PLC), a membrane-associated enzyme that catalyses the production of 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) from hydrolysing phosphoinositol 4,5-bisphosphate (PIP2). This results in a higher concentration of cytosolic Ca2+ and therefore the phosphorylation and contraction of myosin light chains. Additionally, DAG induces the movement of protein kinase C (PKC) into the membrane from the cytoplasm and then its activation. PKC is then able to phosphorylate a number of substances, such as calponin. 

Gq also has a role in asthma treatment as GPCRs are the main targets of anti-asthmatic therapy due to the fact that the main inducers of airway smooth muscle contraction or relaxation are ligands of GPCRs. Histamine, cysteinyl leukotrienes, endothelin-1, and bradykinin, which are cell mediators, influence procontractile GPCRs that are coupled to Gq and cause constriction of the airways in the lungs by tightening of surrounding airway smooth muscle. 

Furthermore, Gq facilitates the growth of airway smooth muscle induced by receptor tyrosine kinase by the activation of ribosomal protein S6 kinase beta-1 (p70S6K). Gq can also activate Rho by interacting with guanine-nucleotide exchange factors for Rho (RhoGEFs). In addition, Gq can be activated by thrombin via protease-activated receptors (PARs) and by lysophosphatidic acid (LPA) via endothelium differentiation gene (EDG) receptors. This leads to the synthesis of DNA and the cell division of airway smooth muscle. Other than thrombin and LPA, eukotriene D4 (LTD4), endothelin, histamine, thromboxane, and sphingosine-1-phosphate (SPP) are all agonists for Gq coupled receptors and have been shown to increase the mitogenic effects of the signalling of receptor tyrosine kinase, but it is not confirmed that it is solely due to the activation of Gq. 

Post Author: admin

x

Hi!
I'm Dora!

Would you like to get a custom essay? How about receiving a customized one?

Check it out