GPCR Heterodimerization in the Reproductive System: Functional Regulation and Implication for Biodiversity

Abstract

A G protein-coupled receptor (GPCR) functions not only as a monomer or homodimer but also as a heterodimer with another GPCR. GPCR heterodimerization results in the modulation of the molecular functions of the GPCR protomer, including ligand binding affinity, signal transduction, and internalization. There has been a growing body of reports on heterodimerization of multiple GPCRs expressed in the reproductive system and the resultant functional modulation, suggesting that GPCR heterodimerization is closely associated with reproduction including the secretion of hormones and the growth and maturation of follicles and oocytes. Moreover, studies on heterodimerization among paralogs of gonadotropin-releasing hormone (GnRH) receptors of a protochordate, Ciona intestinalis, verified the species-specific regulation of the functions of GPCRs via multiple GnRH receptor pairs. These findings indicate that GPCR heterodimerization is also involved in creating biodiversity. In this review, we provide basic and current knowledge regarding GPCR heterodimers and their functional modulation, and explore the biological significance of GPCR heterodimerization.

Oligomerization of GPCRs involved in endocrine regulation

“…Evidence of human GnRHR dimerization derives from mutant receptors that inhibit ligand binding and second messenger production of wild-type via a dominant negative effect ( Brothers et al 2004). Interestingly, in the protochordate Ciona intestinalis, which lacks a hypothalamus-pituitary-gonad axis, four different subtypes of GnRHR exist (reviewed in Satake et al 2013). One of the receptor subtypes (R4) is an orphan receptor and modulates the functionality of a further particular GnRHR receptor subtype in terms of intracellular Ca2+ elevation and ERK phosphorylation (Sakai et al 2008).…”

“…Moreover, GnRHR-mediated cAMP signaling is decreased in the heterodimeric constellation between this orphan GnRHR and another paralog due to a shift from Gs to Gi signaling (Sakai et al 2012). However, how GnRHR oligomerization influences the expression and secretion of the gonadotropins LH and FSH has not yet been thoroughly investigated (Satake et al 2013). The receptors for FSH (FSHR) and LH/CG (LHCGR) play a crucial role in reproductive physiology (Themmen & Huhtaniemi 2000).…”

History of the G Protein–Coupled Receptor (GPCR) Assays From Traditional to a State-of-the-Art Biosensor Assay

“…In addition to the classical roles of GPCRs, the concept of homodimeric or heterodimeric GPCRs has gained acceptance in the last few decades (3,7). GPCRs exist in a dynamic equilibrium between a monomeric and dimeric state, and their heterodimerization affects pharmacological and cellular signaling responses differently compared to when only the receptor subtypes are individually expressed (7).…”

“…GPCRs exist in a dynamic equilibrium between a monomeric and dimeric state, and their heterodimerization affects pharmacological and cellular signaling responses differently compared to when only the receptor subtypes are individually expressed (7). These novel findings were impossible to discover without the development of sophisticated assay for GPCRs (3).…”

Posttranslational Modification of Intercellular Messenger Systems

“…This Research Topic is aimed to assemble a series of review articles and original research papers on structural analysis or functional significance of posttranslational modification of/by intercellular messengers, including hormonal messengers and gaseous messengers, in vertebrates and invertebrates: posttranslational modification of peptide hormones such as proopiomelanocortin (1, 2), ghrelin (3)(4)(5), and hormonal receptors and effectors (6)(7)(8). Review articles on gaseous messengers such as hydrogen sulfide (9) and nitric oxide (10) are also included.…”