The LH receptor (LHR) and FSH receptor (FSHR), collectively termed the gonadotropin receptors, are GPCRs that play a pivotal role in reproductive physiology. Recent studies from our laboratory and others suggest that the LHR self-associates into high molecular weight complexes consistent with dimers and oligomers of the receptor. The focus of this grant is to mechanistically and functionally examine the dimerization/oligomerization of the hLHR as well as the closely related hFSHR. In spite of the growing body of evidence that GPCRs exist as dimers/oligomers, the region(s) of a given GPCR mediating dimerization appear varied and the functional role(s) of the dimers/oligomers remains enigmatic. We propose to utilize novel and complementary approaches to address these questions as they relate to gonadotropin receptor dimerization/oligomerization. In addition, given the precedence for hetero-dimerization/oligomerization between different GPCRs, the high degree of homology between the hLHR and hFSHR, and the expression of both the hLHR and hFSHR in differentiated granulosa cells, a particularly relevant question we will also address is whether the hLHR and hFSHR form hetero-dimers/oligomers and what the functional ramifications of this are.
The specific aims of the grant, therefore, are to: (1) determine the functional role(s) of cell surface gonadotropin receptor dimerization; (2) determine if the hLHR and hFSHR hetero-dimerize and, if so, examine the functional consequences of this phenomenon; and (3) determine the structural region(s) mediating homo- and hetero-dimerization of the gonadotropin receptors. Overall, the proposed studies in the grant will contribute novel and significant insights into homo- and heterodimerization/oligomerization of the gonadotropin receptors, providing new paradigms for the roles of these receptors in reproductive endocrinology.
|Feng, Xiuyan; Zhang, Meilin; Guan, Rongbin et al. (2013) Heterodimerization between the lutropin and follitropin receptors is associated with an attenuation of hormone-dependent signaling. Endocrinology 154:3925-30|
|Segaloff, Deborah L (2012) Regulatory processes governing the cell surface expression of LH and FSH receptors. Subcell Biochem 63:113-29|
|Zhang, Meilin; Guan, Rongbin; Segaloff, Deborah L (2012) Revisiting and questioning functional rescue between dimerized LH receptor mutants. Mol Endocrinol 26:655-68|
|Guan, Rongbin; Wu, Xueqing; Feng, Xiuyan et al. (2010) Structural determinants underlying constitutive dimerization of unoccupied human follitropin receptors. Cell Signal 22:247-56|
|Segaloff, Deborah L (2010) Constitutive activity of the lutropin receptor and its allosteric modulation by receptor heterodimerization. Methods Enzymol 484:231-52|
|Guan, Rongbin; Feng, Xiuyan; Wu, Xueqing et al. (2009) Bioluminescence resonance energy transfer studies reveal constitutive dimerization of the human lutropin receptor and a lack of correlation between receptor activation and the propensity for dimerization. J Biol Chem 284:7483-94|
|Segaloff, Deborah L (2009) Diseases associated with mutations of the human lutropin receptor. Prog Mol Biol Transl Sci 89:97-114|
|Tao, Ya-Xiong; Segaloff, Deborah L (2009) Follicle stimulating hormone receptor mutations and reproductive disorders. Prog Mol Biol Transl Sci 89:115-31|
|Zhang, Meilin; Feng, Xiuyan; Guan, Rongbin et al. (2009) A cell surface inactive mutant of the human lutropin receptor (hLHR) attenuates signaling of wild-type or constitutively active receptors via heterodimerization. Cell Signal 21:1663-71|