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CNA Seminar/Colloquium/Joint Pitt-CNA Colloquium
Luca Deseri
University of Trento
Title: TBA

Abstract: Conformational changes of transmembrane domains of beta-adrenergic re- ceptors have been observed at the onset of production of cyclic Adenosine MonoPhosphate (cAMP) [1]. Often times such changes may be accompanied by shortening or elongating of lipids forming the cell membranes and/or shearing of them across the thickness of the membrane itself. The pathway mentioned above may be detected through measurements of cAMP. This is an intracellular second messenger that transduces inside the cell the effects of extracellular ligands, which cannot get through the cell mem- brane. Such ligands bind to a specific receptor, following the so called ”key mechanism lock principle”. Beta-adrenergic receptors are essentially integral membrane proteins embedded in the lipid bilayer and they belong to the so called G protein-coupled receptor (GPCR) family, which is characterized by seven transmembrane helices, denoted by T M i, i = 1, 2, ..., 7 (see e.g. [2]). The conformational changes mentioned above may involve both a rotation about the axis of TM6 and a shear of TM6 towards TM5. Once the ligand is recognized, the receptor changes conformation and activates the so called G protein; this detaches from the receptor and, in turn, activates another membrane protein, called adenylyl cyclase. This enzyme transforms adenosine triphosphate (ATP) in cAMP. The cyclic nucleotide works by activating protein kinase A that trans- fers a phosphate group into other proteins involved in several cell functions, in- cluding proliferation and migration. This may be observed in human trophoblast cells (see e.g. [3], [4], [5]) forming the fetal site of the placenta. The response of aggregates of such cells to epinephrine is detected through enhancement of cAMP, which is involved in the control of human extravillous trophoblast cell proliferation and migration [3]. Indeed, prostaglandin E2 (PGE2) and forskolin (FSK), two compounds that highly enhance cAMP concentration, inhibit cell proliferation and migration, whereas somatostatin, which reduces PGE2- and FSK-enhanced cAMP levels, stimulates these responses [4], [5]. It then becomes crucial to be able to make predictions about the cell response to a given ligand and, hence, to the associated conformational and mechanical changes.

The main features of a predictive model for the are outlined in this paper. The second messenger response turns out to be directly linked to the coupling of conformational and mechanical effects arising from the new Helmholtz free energy derived for such a system. The evaluation of its stationary points together with the balance between the influx of active receptors and the rate of their density change yield the desired result.

References:

[1] Ghanouni, P., Steenhuis, J.J., Farrens, D.L. and Kobilka, B.K., ”Agonist- induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor”, Proc. Nat.l. Acad. Sci. USA, 98(11), 5997-6002 (2001).

[2] Cherezov, V., Rosenbaum, D.M., Hanson, M.A., Rasmussen, S.G., Thian, F.S., Kobilka, T.S., Choi, H.J., Kuhn, P., Weis, W.I., Kobilka, B.K. and Stevens, R.C., ”High-resolution crystal structure of an engineered human beta-2- adrenergic G protein-coupled receptor”, Science, 318(5854), 1258-65 (2007).

[3] Lunghi, L., Ferretti, M.E., Medici, S., Biondi, C. and Vesce, F., ”Control of human trophoblast function”, Reprod Biol Endocrinol., 8, 6-14. Review (2007).

[4] Biondi, C., Ferretti, M.E., Pavan, B., Lunghi, L., Gravina, B., Nicoloso, M.S., Vesce, F. and Baldassarre, G., ”Prostaglandin E2 inhibits proliferation and migration of HTR-8/SVneo cells, a human trophoblast-derived cell line”, Placenta, 27(6-7), 592-601 (2006).

[5] Biondi, C., Ferretti, M.E., Lunghi, L., Medici, S., Cervellati, F., Abelli, L., Bretoni, F., Adinolfi, E., Vesce, F., Bartolini, G., Papi, A., D’Andrea, S., Berton, S. and Baldassarre, G., ”Somatostatin as a regulator of first-trimester human trophoblast functions”, Placenta, 29(8), 660-70 (2008).

[6] Lunghi L., Deseri, L. Biondi, C., Ferretti, M.E., ”Response of cell aggregates to ligands: a predictive model based on conformational and mechanical effects”, in preparation.

[7] Deseri, L., Piccioni, M. D., Zurlo, G., ”Derivation of a new free energy for biological membranes”, Cont. Mech. Thermodyn., 20 (5), 255-27 (2008).

[8] Gao, H., Shi, W., Freund, L. B., ”Mechanics of receptor mediated endocy- tosis”, Proc. Nat.l. Acad. Sci. USA, 102 (27), 9469-9474 (2005).

[9] Finkelstein, A. V., Janin, J. ”The price of lost freedom: entropy of bimolec- ular complex formation”, Protein Engineering, 3 (1), 1-3 (1989).

Date: Thursday, November 4, 2010
Time: 1:30 pm
Location: Wean Hall 8220
Submitted by:  David Kinderlehrer