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Regulatory Processes Governing the Cell Surface Expression of LH and FSH Receptors

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GPCR Signalling Complexes – Synthesis, Assembly, Trafficking and Specificity

Part of the book series: Subcellular Biochemistry ((SCBI,volume 63))

Abstract

The LH receptor (LHR) and FSH receptor (FSHR), collectively termed the gonadotropin receptors, are members of the Family A of GPCRs. The gonadotropin receptors each contain N-linked carbohydrates that are not directly involved in hormone binding, but contribute to the proper folding, and therefore, cell surface expression of the receptor. Loss-of-function mutations of an LHR or FSHR results in decreased target cell responsiveness. Most inactivating mutations cause receptor misfolding, resulting in the retention of the mutant in its immature form in the endoplasmic reticulum. A membrane-permeable allosteric agonist of the LHR has been shown to serve as a pharmacological chaperone for misfolded and intracellularly retained LHRs by promoting their cell surface expression. Wild-type LHR and FSHR each form homodimers and heterodimers while in the ER. Therefore, when wild-type receptor is co-expressed with a misfolded mutant, the misfolded receptor dimerizes with immature wild-type receptor in the ER, causing a dominant-negative effect on cell surface expression of the mature wild-type receptor. Notably, the propensity for homodimerization is not affected by the activation status of the receptor. However, within a receptor dimer, the activity of one protomer may allosterically regulate the other protomer. Therefore, the dimerization of the gonadotropin receptors appears to be an obligate process that is part of the normal itinerary for trafficking to the cell surface and, once there, the dimerized receptors allow for additional modulations of cell signaling.

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Acknowledgements

Studies from the author’s laboratory discussed herein were supported by NIH grants HD022196 and DK068614.

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  1. Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Deborah L. Segaloff

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  1. Deborah L. Segaloff
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Correspondence to Deborah L. Segaloff .

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Editors and Affiliations

  1. Faculty of Medicine, Pharmacology, Dalhousie University, College Street 5968, Halifax, B3H 4R2, Nova Scotia, Canada

    Denis J. Dupré

  2. , Pharmacology and Therapeutics, McGill University, Promenade Sir William Osler 3655, Montreal, H3G 1Y6, Québec, Canada

    Terence E. Hébert

  3. Institut Cochin, Rue Méchain 22, Paris, 75014, France

    Ralf Jockers

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© 2012 Springer Science+Business Media Dordrecht

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Segaloff, D.L. (2012). Regulatory Processes Governing the Cell Surface Expression of LH and FSH Receptors. In: Dupré, D., Hébert, T., Jockers, R. (eds) GPCR Signalling Complexes – Synthesis, Assembly, Trafficking and Specificity. Subcellular Biochemistry, vol 63. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4765-4_7

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