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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068614-03
Application #
7262519
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Malozowski, Saul N
Project Start
2005-09-15
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$244,750
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Zhang, Meilin; Guan, Rongbin; Segaloff, Deborah L (2012) Revisiting and questioning functional rescue between dimerized LH receptor mutants. Mol Endocrinol 26:655-68
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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
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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