Deborah L. Segaloff, Ph.D.

Professor

Faculty Member: Holden Comprehensive Cancer Center

Vanderbilt University, 1980

Research Interests

G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors, regulating a wide array of physiological processes. My laboratory is interested in the mechanism of action of GPCRs, focusing primarily on the LH and FSH receptors (gonadotropin receptors), which play a pivotal role in reproductive endocrinology. The gonadotropin receptors, as well as the structurally related TSH receptor, are composed of a 7TM region that shares homology with the rhodopsin family of GPCRs as well as a large extracellular domain. By mechanisms not yet well understood, the binding of hormone to the extracellular domain of the LH, FSH, or TSH receptor stabilizes the receptor in an active state such that the 7TM region can then activate G proteins (primarily Gs). Constitutively activating mutations of these receptors also stabilize the receptor in an active state. We are exploiting differences in the functional activities of the LH, FSH, and TSH receptors (basal, mutation-induced, and hormone-stimulated) to identify the structural features of the receptors that mark their resting versus active states. We are also studying the homo- and hetero-dimerization of the LH and FSH receptors. By co-immunoprecipitation of differentially tagged LHR receptors solubilized from cells, we had previously shown that the LH receptor constitutively forms dimers and higher ordered oligomers. We are currently using resonance energy transfer techniques to examine the homo- and hetero-dimerization of the LH and FSH receptors in living cells. Experiments are aimed at elucidating the functional role(s) of dimerization, the ontogeny of gonadotropin dimer formation, and the structural regions mediating receptor dimerization.

Representative References

Zhang, M., Mizrachi, D., Fanelli, F. and Segaloff, D.L. The formation of a salt bridge between helices 3 and 6 is responsible for the constitutive activity and lack of hormone responsiveness of the naturally occurring L457R mutation of the human lutropin receptor. J. Biol. Chem., 280:26169-26176, 2005.

Latronico, A.C. and Segaloff, D.L. Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor. Mol. Cell. Endocrinol.260-262:287-293, 2007.

Freitas, K.C.M., Ryan, G., Brito, V.N., Tao, Y.-X., Mendonca, B.B., Segaloff, D.L., and Latronico, A.C. Molecular analysis of the neuropeptide Y1 receptor gene (NPY-Y1R) in human idiopathic gonadotropin-dependent precocious puberty and isolated hypogonadotropic hypogonadism. Fert. Ster., 87:627-634, 2007.

Ryan, G.L., d’Alva, C.B., Zhang, M., Van Voorhis, B.J., Pinto, E.M., Kubias, A.E.F., Antonini, S.R., Latronico, A.C., and Segaloff, D.L. FSH receptor polymorphisms do not explain gonadal hyperstimulation associated with severe juvenile primary hypothyroidism: evidence for direct stimulation of the FSH receptor by elevated concentrations of TSH. J. Clin. Endocrinol. Metabol., 92:2312-2317, 2007.

Zhang, M., Tao, Y.-X., Ryan, G.L., Fang, X., Fanelli, F., and Segaloff, D.L. Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations, J. Biol. Chem., 282:25527-25539, 2007.