Jump to content

User:Am723007/sandbox

From Wikipedia, the free encyclopedia

Medical implications[edit]

Drug design[edit]

The βγ subunit plays a variety of roles in cell signalling processes and as such researchers are now examining its potential as a therapeutic drug target for the treatment of many medical conditions. However it is recognized that there are a number of considerations to keep in mind when designing a drug which targets the βγ subunit:

1) The βγ subunit is essential for the formation of heterotrimeric G protein through its association with the Gα subunit allowing the G proteins coupling to the GPCR. Therefore any agent inhibiting the By subunits signalling effects must not interfere with the heterotrimeric G protein formation or Gα subunit signalling.

2) Gβγ expression is universal throughout almost all the cells of the body so any agent acting to inhibit this subunit could elicit numerous side effects.

3) Small molecule inhibitors that target the coupling of Gβγ to specific effectors and do not interfere with normal G protein cycling/ heterotrimeric formation, have the potential to work as therapeutic agents in treating some specific diseases.[1]

Targeting the Gβγ subunit in treatment:[edit]

Research has been conducted on how altering the actions of βγ subunit could be beneficial for the treatment of certain medical conditions.Gβγ signalling has been examined for its role in a variety of conditions including heart failure, inflammation and leukemia.The examples presented here are only a sampling of the multiple effectors in different medical conditions which may be targeted by a therapeutic agent that inhibits Gβγ.[1] [2] The potential of targeting the βγ subunit for the treatment of three conditions will be discussed in more detail below.

1) Heart failure:[edit]

Heart failure can be characterized by a loss of β adrenergic receptor (βAR) signalling in heart cells.[3] When the βAR is stimulated by catecholamines such as adrenalin and noradrenalin normally there is an increase in the contractility of the heart. However in heart failure there are sustained and elevated levels of catecholamines which result in chronic desensitization of the βAR receptor. This leads to a decrease in the strength of heart contractions. Some research suggests that this chronic desensitization is due to the over activation of a kinase, G protein-coupled receptor kinase 2 (GRK2), which phosphorylates and deactivates certain G protein coupled receptors .[4] When the G protein coupled receptor is activated, the βγ subunit recruits GRK2 which then phosphorylates and desensitizes GPCRs like the βAR. [5] Preventing the interaction of the βγ subunit with GRK2 has therefore been studied as a potential target for increasing heart contractile function. The developed molecule GRK2ct is a protein inhibitor which inhibits the signalling properties of Gβγ subunit but does not interfere with alpha subunit signalling.[6] The over expression of GRK2ct has been shown to significantly rescue cardiac function in murine models of heart failure by blocking βγ subunit signalling.[7] Another study took biopsies from patients with heart failure and virally induced overexpression of GRK2ct in the heart myocytes. They also found an improvement in cardiac cell contractile function by inhibiting Gβγ.[8]

2) Inflammation:[edit]

When particular GPCRs are activated by their specific chemokines Gβγ directly activates PI3Kγ which is involved in the recruitment of neutrophils that contribute to inflammation. [9][10][11][12] It has been discovered that the inhibition of PI3Kγ significantly reduces inflammation.[9] [10] PI3Kγ is the intended target molecule in the prevention of inflammation as it is the common signalling effector of many different chemokine and receptor types involved in promoting inflammation. [11][12] Although PI3Kγ is the intended target there are other isoforms of PI3 which perform different functions from PI3Kγ. Since PI3Kγ is specifically regulated by Gβγ, while other isoforms of PI3 are largely regulated by other molecules,inhibiting Gβγ signalling would provide the desired specificity of a therapeutic agent designed to treat inflammation.[1]

3) Leukemia:[edit]

The Gβγ subunit has been shown to activate a Rho guanine nucleotide exchange factor (RhoGef) gene PLEKHG2 which is upregulated in a number of leukemia cell lines and mouse models of leukemia. Lymphocyte chemotaxis as a result of Rac and CDC42 activation as well as actin polymerization is believed to be regulated by the Gβγ activated RhoGef. Therefore a drug inhibiting the Gβγ could play a role in the treatment of leukemia.[2]

References[edit]

  1. ^ a b c Lin Y., & Smrcka A. V.(2011).Understanding Molecular Recognition by G protein Subunits on the Path to Pharmacological Targeting . Mol Pharmacol, 80(4)doi: 80:551–557
  2. ^ a b Runne, C. & Chen S.(2013).PLEKHG2 Promotes Heterotrimeric G Protein bg-Stimulated Lymphocyte Actin Polymerization Migration via Rac and Cdc42 Activation and Migration via Rac and Cdc42 Activation. Mol. Cell. Biol., 33(21),4294. doi: 10.1128/MCB.00879-13.
  3. ^ Brodde, O. E. & Michel, M. C. (1999).Adrenergic and muscarinic receptors in the human heart. Pharmacol.,51(4),651-90. doi: 10581327
  4. ^ Hata, J. A. & Koch, W. J.(2003).Phosphorylation of G protein-coupled receptors: GPCR kinases in heart disease.Mol. Interv,3,264-72. doi:14993440
  5. ^ Pitcher, J. A., Inglese, J., Higgins, J. B., Arriza, J. L., Casey, P.J., Kim, C., Benovic, J. L., Kwatra, M. M., Caron, M.G. & Lefkowitz, R. J.(1992).Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors.Science, 257,1264. doi: 1325672
  6. ^ Koch, W.J., Hawes, B.E., Inglese, J., Luttrell, L. M. & Lefkowitz, .R J. J. (1994).Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signaling.Biol. Chem, 269,6193. doi: 8119963
  7. ^ Rockman, H. A., Chien, K. R., Choi, D. J., Iaccarino, G., Hunter, J. J., Ross, J. Jr., Lefkowitz, R. J. & Koch, W. J.(1998).Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.Proc. Natl. Acad. Sci., U.S.A, 95(12),7000-5.doi:9618528
  8. ^ Williams, M. L., Hata, J. A., Schroder, J., Rampersaud, E., Petrofski, J., Jakoi, A., Milano, C.A. & Koch, W. J.(2004).Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts.Circulation, 109,1590.doi:15051637
  9. ^ a b Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A. V. & Wu, D.(2000).Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction.Science, 287,1046.doi: 10669417
  10. ^ a b Hirsch, E., Katanaev, V. L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F. & Wymann, M. P. (2000).Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation.Science, 287,1049.doi:10669418
  11. ^ a b Stephens, L. R., Erdjument-Bromage, H., Lui, M., Cooke, F., Coadwell, J., Smrcka, A. V., Thelen, M., Cadwallader, K., Tempst, P. & Hawkins, P. T.(1997).The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101.Cell, 89,105.doi:9094719
  12. ^ a b Stephens, L., Smrcka, A., Cooke, F. T., Jackson, T. R., Sternweis, P. C. & Hawkins, P. T. (1994).A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits.Cell, 77,83. doi:8156600
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Am723007/sandbox&oldid=602210389"