Date of Award

6-2018

Document Type

Union College Only

Degree Name

Bachelor of Science

Department

Neuroscience

First Advisor

Brian Cohen

Language

English

Keywords

GPCR, FSH, peptide, allosteric modulation, FSHR, caveolin, lipid rafts

Abstract

Follicle stimulating hormone (FSH) plays an integral role in the maturation of gametes in both males and females, making it a target for both contraceptive and fertility research. This heterodimeric protein hormone acts on a g protein-coupled receptor aptly named the follicle stimulating hormone receptor (FSHR), which is expressed in testicular Sertoli and ovarian granulosa cells. This receptor has been known to associate with cholesterol and sphingolipid-rich membrane domains called lipid rafts as well as the membrane protein caveolin, which act to regulate signaling. The binding of the hormone to its receptor activates an intracellular signaling cascade which as traditionally been considered to be mainly cAMP-dependent. However, recent research has indicated that the actual mechanism of action of FSHR's signaling may be far more complicated than previously considered. In this work, small molecule modulators were used to attempt to more clearly characterize the intricacies of receptor signaling. First, peptide mimetic of the receptor's caveolin interaction motif were used to examine the interaction between caveolin and the receptor complex. Second, downstream signaling after administration of negative allosteric modulators (NAMs) known to inhibit FSHR signaling was examined to determine where in the signaling cascade inhibition is evident. Western blotting was used to compare relative amounts of secondary messenger activation. Results suggest that caveolin has an inhibitory action on the receptor, and generally, small molecules have the ability to modulate receptor action. Better understanding of this signaling pathway may eventually enable the development of more targeted pharmaceuticals for both contraception and fertility.

Available for download on Friday, June 14, 2019

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