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Dual positive and negative regulation of GPCR signaling by GTP hydrolysis

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Smith, Benjamin, Hill, Claire, Godfrey, Emma L., Rand, D. A. (David A.), Berg, Hugo van den, 1968-, Thornton, Steve, Hodgkin, Matthew N., Davey, John and Ladds, Graham . (2009) Dual positive and negative regulation of GPCR signaling by GTP hydrolysis. Cellular Signalling, Vol.21 (No.7). pp. 1151-1160. ISSN 0898-6568

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Official URL: http://dx.doi.org/10.1016/j.cellsig.2009.03.004

Abstract

G protein-coupled receptors (GPCRs) regulate a variety of intracellular pathways through their ability to promote the binding of GTP to heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins increase the intrinsic GTPase activity of G-subunits and are widely regarded as
negative regulators of G protein signaling. Using yeast we demonstrate that GTP hydrolysis is not only required for desensitization, but is essential for achieving a high maximal (saturated level) response. Thus RGS-mediated GTP hydrolysis acts as both a negative (low stimulation) and
positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where GGTP enters an inactive GTP-bound state following effector activation. Furthermore, in vivo and in silico experimentation demonstrates that maximum signaling output first increases and then decreases with RGS concentration. This unimodal, non-monotone
dependence on RGS concentration is novel. Analysis of the kinetic model has revealed a dynamic network motif that shows precisely how inclusion of the inactive GTP-bound state for the G produces this unimodal relationship.

Item Type:	Journal Article
Subjects:	Q Science > QR Microbiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Science > Molecular Organisation and Assembly in Cells (MOAC) Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	G proteins, Computer simulation
Journal or Publication Title:	Cellular Signalling
Publisher:	Elsevier Inc.
ISSN:	0898-6568
Official Date:	July 2009
Volume:	Vol.21
Number:	No.7
Number of Pages:	10
Page Range:	pp. 1151-1160
Identification Number:	10.1016/j.cellsig.2009.03.004
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), University Hospitals Coventry and Warwickshire NHS Trust
Grant number:	BB/G01227X/1 (BBSRC)
References:	1. S.R. Sprang, Annu. Rev. Biochem. 66 (1997) 639-678. 2. C.A. Johnston, D.P. Siderovski, Mol. Pharmacol. 72 (2007) 219-230. 3. E.M. Ross, T.M. Wilkie, Annu. Rev. Biochem. 69 (2000) 795-827. 4. G.B. Willars, Semin. Cell. Dev. Biol. 17 (2006) 363-376. 5. G. Ladds, J. Davey, Trends Biotechnol 23 (2004) 367-373. 6. J. Davey, Yeast 14 (1998) 1529-1566. 7. H.G. Dohlman, Annu. Rev. Physiol. 64 (2002) 129-152. 8. H.G Dohlman, Thorner, J. J. Biol. Chem. 272 (1997) 3871-3874. 9. C.S. Hoffman, Eukaryot. Cell. 4 (2005) 495-503. 10. T. Obara, M. Nakafuku, M. Yamamoto, Kaziro, Y. Proc. Natl. Acad. Sci. USA 88 (1991) 5877-5881. 11. C. Hill, A. Goddard, J. Davey, G. Ladds, Semin. Cell. Dev. Biol. 17 (2006) 352-362. 12. G. Ladds, A. Goddard, C. Hill, S. Thornton, J. Davey, Cell. Signal. 19 (2007) 103-113. 13. J. Davey, EMBO J. 11 (1991) 951-960. 14. P. Watson, K. Davis, M. Didmon, P. Broad, J. Davey, Mol. Microbiol. 33 (1999) 623-634. 15. P.S. Pereira, N.C. Jones, Genes. Cells. 6 (2001) 789-802. 16. M. Didmon, K. Davis, P. Watson, G. Ladds, P. Broad, Davey, J. Curr Genet 41 (2002) 241- 253. 17. G. Ladds, K. Davis, A. Das, J. Davey, Mol. Microbiol. 55 (2005) 482-497. 18. J. Davey, R. Egel, O. Nielsen, in Adolph KW (Ed), Methods in Molecular Genetics, Pheromone procedures in fission yeast, San Diego, 1995, pp. 247-263. 19. G. Ladds, E.M. Rasmussen, T. Young, O. Nielsen, J. Davey, Mol. Microbiol. 20 (1996) 35-42. 20. G. Ladds, K. Davis, E.W. Hillhouse, J. Davey, Mol. Microbiol. 47 (2003) 781-792. 21. K. Maundrell, Gene 123 (1993) 127-130. 22. K. Davis, G. Ladds, A. Das, A. Goddard, Davey, J. Mol. Biotechnol. 28 (2004) 201-204. 23. P. DiBello, T. Runyan-Garrison, D.M. Apanovitch, G. Hoffman, D.J. Shuey, K. Mason, M.I. Cockett, H.G. Dohlman, J. Biol. Chem. 273 (1998) 5780-5784. 24. S. Landry, M.T. Pettit, E. Apolinario, C.S. Hoffman, Genetics 154 (2000) 1463-1471. 25. J.J. Carrillo, P.A. Stevens, G. J. Milligan, Pharmacol. Exp. Ther. 302 (2002) 1080-1088. 26. H. Zhong, S.M. Wade, P.J. Woolf, J.L. Linderman, J.R.Traynor, R.R. Neubig, J. Biol. Chem. 278 (2003) 7278-7284. 27. N. Hao, N. Yildirim, Y. Wang, T.C. Elston, H.G. Dohlman, J. Biol. Chem. 278 (2003) 46506- 46515. 28. B. Kofahl, E. Klipp, Yeast 21 (2004) 831-850. 29. N. Yildirim, N. Hao, H.G. Dohlman, T.C. Elston, Methods Enzymol. 389 (2004) 383-398. 30. S.J. Bornheimer, M.R. Maurya, M.G. Farquhar, S. Subramaniam, Proc. Natl. Acad. Sci. USA 101 (2004) 15899-15904. 31. A.B. Goryachev, A.V. Pokhilko, PLoS Comput. Biol. 2 (2006) 1511-1521. 32. M. Turcotte, W. Tang, E.M. Ross, PLoS Comput. Biol. 4 (2008) e1000148. 33. J.J. Linderman, J. Biol. Chem. (2008) DOI: 10.1074/jbc.R800028200. 34. T.I. Moore, C.C. Chou, Q. Nie, N.L. Jeon, T. Yi, PLoS ONE 3 (2008)e3865. 35. U. Alon, Nature 446 (2007) 497. 36. A.G. Gilman, Annu. Rev. Biochem. 56 (1987) 615-649. 37. B. Cook, M. Bar-Yaacov, H.C. Ben-Ami, R.E. Goldstein, Z. Paroush, Z. Selinger, B. Minke, Nat. Cell. Biol. 2 (2000) 296-301. 38. N. Hao, S. Nayak, M. Behar, R.H. Shanks, M.J. Nagiec, B. Errede, J. Hasty, T.C. Elston, H.G. Dohlman, Mol. Cell. 30 (2008) 649-656. 39. D.R. Ballon, P.L. Flanary, D.P. Gladue, J.B. Konopka, H.G. Dohlman, J. Thorner, Cell 126 (2006) 1079-1093. 40. G. Milligan, Trends Endocrinol. Metab. 9 (2008) 13-19. 41. C.A. Doupnik, N. Davidson, H.A. Lester, and P. Kofuji, Proc. Natl. Acad. Sci. USA 94 (1997) 10461-10466. 42. O. Saitoh, Y. Kubo, M. Odagiri, M. Ichikawa, K. Yamagata, T. Sekine, J. Biol. Chem. 274 (1997) 9899-9904. 43. N. Zerangue, L.Y. Jan, Curr. Biol. 8 (1998) R313-R316. 44. S.W. Jeong, S.R. Ikeda, J. Neurosci. 20 (2000) 4489-4496. 45. A. Tinker, Semin. Cell. Dev. Biol. 17 (2006) 377-382. 46. R.K. Chan, C.A. Otte, Mol. Cell. Biol. 2 (1982a) 21-29. 47. R.K. Chan, C.A. Otte, Mol. Cell. Biol. 2 (1982b) 11-20. 48. H.G. Dohlman, D. Apaniesk, Y. Chen, J. Song, D. Nusskern, Mol. Cell. Biol. 15 (1995) 3635- 3643.
URI:	http://wrap.warwick.ac.uk/id/eprint/485