The lutropin/choriogonadotropin receptor (LHR) and follitropin receptor (FSHR), collectively termed the gonadotropin receptors, are members of the superfamily of G protein-coupled receptors (GPCRs). The pivotal importance of the gonadotropin receptors in reproductive physiology is underscored by the recent discoveries of pathologies associated with naturally occurring mutations of their genes. For example, many cases of gonadotropin-independent precocious puberty have been found to be attributable to mutations within the hLHR gene causing the hLHR to be constitutively active (i.e., active in the absence of hormone). Interestingly, when the equivalent mutations are introduced into the structurally similar hFSH constitutive activation is not necessarily observed. The studies proposed herein are a continuation of ongoing studies on the structure and function of the gonadotropin receptors, with a particular emphasis on understanding their mechanism of activation.
The aims of this proposal are to: 1. Determine if the ligand-independent activated state(s) of the hLHR are distinct from the agonist-dependent activated state of the hLHR. 2. Determine the mechanisms for the apparent resistance of the hFSHR to mutation-induced ligand-independent activation. 3. Determine the intrinsic activities of the wild-type gonadotropin receptors, activating mutants, and signaling- impaired mutants utilizing a reconstitution assay system consisting of purified receptor and purified Gs. 4. Investigate the possible agonist-dependent self-association of the gonadotropin receptors and whether this self-association is required for receptor activation. The results of these studies will contribute not only to our general understanding of GPCRs, but will also give us greater insights into reproductive physiology. Long term goals of research in this area include the ability to better understand, diagnose, and correct reproductive disorders.
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