The tale of follitropin receptor diversity: A recipe for fine tuning gonadal responses?

doi:10.1016/j.mce.2005.11.052

Molecular and Cellular Endocrinology

Volumes 260–262, 2 January 2007, Pages 163-171

https://doi.org/10.1016/j.mce.2005.11.052 Get rights and content

Abstract

The original concept (dogma) of a single FSH receptor entity coupling to G_s protein to activate adenylate cyclase and producing cAMP as second messenger appears inadequate to explain pleiotropic actions of the hormone. The identification and expression of alternatively spliced gonadotropin receptors, suggest that alternative splicing could serve as a mechanism for creating receptor diversity. Studies focused on sheep and mouse gonadal tissues show that the single large gene of ∼250 kb is a modular structure whose pre-mRNA undergoes alternative splicing creating several subtypes (at least four FSH-R1 to R4 identified to date). With segments of the N-terminus that are identical different topographies are generated by differing carboxyl termini. The same gene thus produces receptor types with different motifs that can display dominant positive, dominant negative, growth factor/cytokine type and potentially soluble binding protein features. Functional relevance is shown by modulation of receptor variants during hormonal stimulation. Presence of equivalent segments of the gene in the human and bovine suggests conservation and predicts similarity in structures and function. Thus, the complex cellular biology of follitropin receptors that may interact differently with polymorphic forms (glycosylation variants) of FSH represents an intricate scheme to regulate hormone signaling.

Section snippets

Introduction: so few genes and myriad of proteins

The number of genes in the human genome and other mammals is steadily decreasing from previous projections of more than 100–150,000 in the pre-genome era to as few as 23,000 estimated or identified by the end of 2004 when refined sequence data became available (International Human Genome Sequencing Consortium, 2004). How could such a small number that is about the same as the tiny flowering plant Arabidopsis or slightly more than the lowly worm Caenorhabditis elegans, account for the complexity

Acknowledgements

Investigations emanating from this laboratory have received support from the CIHR and NCI of Canada. Our apologies for not citing all papers in this area and these can be found in review articles.

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In mouse ovaries, mRNA expression of FSHR3 was also greater than FSHR1 [29]. Furthermore, it has been suggested that FSHR variants may play different roles depending on gonadal development and functions [23,29]. However, these hypotheses require further study.
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The gonads (ovary, testis) produce gametes (oocytes and spermatozoa). The pituitary glycoprotein hormones luteinizing hormone (LH, lutropin) and follicle-stimulating hormone (FSH, follitropin) are gonadotropins because their targets are the gonads. Another hormone produced by the syncytiotrophoblast of the human placenta is human chorionic gonadotropin (hCG, choriogonadotropin), and its activity is like LH. This review describes the protein structure, gene structure, and regulation of biosynthesis of both the gonadotropins and their membrane bound receptors. The functions of both hormones and receptors are covered extensively, as well as naturally occurring mutations that have been identified in disease states and therapies derived from their study.
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A splice variant of LHR that lacks exon 9 has also been reported in human (Minegishi et al., 2007; Nakamura et al., 2004). In the case of FSHR, up to four alternatively spliced transcripts have been described in the ovary (reviewed in (O’Shaughnessy et al., 1996; Sairam and Babu, 2007; Simoni et al., 1997), the expression of which varied at different stages of artificially induced ovulatory cycles (Yaron et al., 1998). More recently, four abnormal FSHR splice variants with reduced responsiveness to FSH have been reported in the cumulus cells surrounding the oocytes isolated from human follicular aspirates (Gerasimova et al., 2010).
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^☆: The terms follitropin and FSH are used interchangeably in this article.

¹: Current address: Lundbeck Research USA, Inc., Paramus, NJ 07652, USA.

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The tale of follitropin receptor diversity: A recipe for fine tuning gonadal responses?☆

Abstract

Section snippets

Introduction: so few genes and myriad of proteins

Acknowledgements

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Trends Biochem. Sci.

Induction of promiscuous G protein coupling of the follicle stimulating hormone (FSH) receptor: a novel mechanism for transducing pleiotropic action of FSH isoforms

Mol. Endocrinol.

Hormone-induced receptor gene-splicing: enhanced expression of the growth factor type I follicle-stimulating hormone receptor motif in the developing mouse ovary as a new paradigm in growth regulation

Endocrinology

Growth hormone binding to a circulating receptor fragment: the concept of receptor shedding and receptor splicing

Exp. Clin. Endocrinol.

A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor

J. Clin. Invest.

Amino-terminal leucine rich repeats in gonadotropin receptors determine hormone selectivity

EMBO J.

Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha

Nature

Gonadotropin induction of C-FOS and C-Myc expression and deoxyribonucleic acid synthesis in rat granulosa cells

Endocrinology

Identifying protein interactors in gonadotropin action

Endocrine

Structure of human follicle-stimulating hormone in complex with its receptor

Nature

Three-dimensional structure of human follicle-stimulating hormone

Mol. Endocrinol.

Follicle-stimulating hormone receptor-mediated uptake of 45Ca2+ by cultured rat Sertoli cells does not require activation of cholera toxin- or pertussis toxin-sensitive guanine nucleotide binding proteins or adenylate cyclase

Endocrinology

An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH-like activity in gonadotropin-deficient transgenic mice

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Patterns of 3H-thymidine incorporation differ in immature rats and mature cycling rats

Biol. Reprod.

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Finishing the euchromatic sequence of the human genome

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Modulation of basal and FSH-dependent cyclic AMP production in rat seminiferous tubules by an improved transillumination technique

Anat. Rec.

Recognition of follicle stimulating hormone (alpha subunit) by a recombinant receptor protein domain coded by an alternately spliced messenger RNA and expressed in E. coli

J. Mol. Endocrinol.

Alternative splicing of follicle-stimulating hormone receptor pre-mRNA: cloning and characterization of two alternatively spliced mRNA transcripts

J. Endocrinol.

Follicle-stimulating hormone receptor-mediated uptake of 45Ca²⁺ by cultured rat Sertoli cells does not require activation of cholera toxin- or pertussis toxin-sensitive guanine nucleotide binding proteins or adenylate cyclase

Patterns of ³H-thymidine incorporation differ in immature rats and mature cycling rats