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.
Highlights
The development of “omics” technologies and ensuring construction of a variety of databases provide vast information regarding primary sequences and functional domains of genes and proteins in diverse organisms, leading to annotation or prediction of biochemical and pharmacological propensities of novel genes and proteins
Recent studies in various fields suggest that G protein-coupled receptor (GPCR) heterodimerization plays crucial roles in the regulation of the HPG axis and the evolution and diversification of reproductive functions
Of special interest is whether kisspeptin receptors or gonadotropininhibitory hormone (GnIH) receptors heterodimerize with any GPCRs
Summary
The development of “omics” technologies and ensuring construction of a variety of databases provide vast information regarding primary sequences and functional domains of genes and proteins in diverse organisms, leading to annotation or prediction of biochemical and pharmacological propensities of novel genes and proteins. Various species-specific GPCRs for highly conserved cognate hormones or neuropeptides have been identified (14–18, Kawada et al, forthcoming) These findings suggest that GPCR heterodimerization participates in the fine-tuning and diversification of reproductive functions. Combined with experimental evidence that ligand binding and signaling of GPCR protomers are altered via heterodimerization, GPCR heterodimerization is believed to induce protomer-specific modulation (i.e., stabilization or instabilization) of active conformations as an endogenous allosteric modulator. This view is compatible with the fact that a single GPCR protomer acquires diverse biochemical and/or pharmacological properties via heterodimerization with different GPCR partners
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