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Mutations in the Human Follicle Stimulating Hormone Receptor Caveolin Binding Motif Cause Increased Basal Activation
Author(s) -
Altman Elizabeth K,
Cohen Brian D
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.797.1
Subject(s) - follicle stimulating hormone receptor , lipid raft , biology , endocrinology , medicine , microbiology and biotechnology , receptor , follicle stimulating hormone , signal transduction , hormone , genetics , luteinizing hormone
Over twelve percent of women aged fifteen to forty‐five in America suffer from infertility and over seven million women have used infertility services, such as intrauterine insemination and in vitro fertilization. Some cases of infertility may be due to dysfunctional human follicle stimulating hormone (hFSH) signaling. hFSH plays a role in spermatogenesis in males, as well as follicle maturation and estrogen production in females. Problems with either hFSH or the hFSH receptor (hFSHR) decrease fertility in males and cause complete infertility in females. As part of the hypothalamic‐pituitary‐gonadal axis, hFSH is released from the pituitary gland and binds to hFSHR in the ovaries and testes. It has been shown that hFSHR interacts with lipid rafts, stiffer regions of the plasma membrane with higher sphingolipid and cholesterol concentrations, and with caveolin, a protein found in certain lipid rafts. This interaction may occur through a specific sequence of amino acids in the 4th transmembrane domain of the hFSHR consistent with a caveolin binding motif (CBM). Previous work from our lab also suggested that hFSHR signaling is regulated through residency in lipid rafts, such that hFSHR signaling is inhibited as a result of recruitment into lipid rafts. The current study investigated the effect of mutations of the CBM on hFSHR signaling. It was hypothesized that complex mutation of the CBM would cause increased hFSHR signaling by disrupting interactions with caveolin, preventing inhibition via residency in lipid rafts. Mutants were created using site‐directed mutagenesis and expression vectors were transiently transfected into HEK293 cells and hFSHR signaling was qualitatively compared between mutants via western blot. Mutation of two sites in the CBM resulted in increased basal and induced hFSHR signaling, yet mutation of three sites decreased signaling below that of the wild type receptor. Mutation of two sites supports the hypothesis, while the decreased signaling from the triple mutant may suggest too large of a conformational change to allow for any receptor function. Further understanding of hFSHR signaling regulation would allow for development of new fertility treatments for men and women. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .