Numerous hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells by binding to G protein-coupled receptors.1 These receptors are seven-transmembrane spanning domain receptors, and belong to the largest superfamily of proteins and regulate the function of virtually every cell.2 As pointed out by their name, these receptors possess an inherent ability of recruiting and regulating the activity of specific heterotri-meric G proteins. These highly specialized transducers are composed of three subunits, one alpha, one beta, and one gamma (a, b, g). They can modulate the activity of multiple signaling pathways leading to diverse biological responses.1 The binding of an endogenous ligand to its cognate G protein-coupled receptor takes place on the cell surface. It may stabilize the receptor on its active conformation or induce a conformational change that activates the downstream signaling pathway regulated by that receptor. Once the receptor is on its active conformation, the a-subunit is released from the heterotrimer originally bound to the receptor. The free a-subunit, in turn, may regulate several signaling pathways inside the cell. These include the modulation of adenylyl cyclase or membrane-bound phospholipases as well as the modulation of ion channels. G protein-coupled receptors play a significant role in body homeostasis, helping keeping vital physiological processes, such as cardiac function, body temperature, blood pressure, brain function, and, of course, reproductive capacity under tight control. Therefore, it is not surprising that abnormal G protein-coupled receptor signaling has been identified as the underlying cause of so many human diseases. Understanding the signaling pathways regulated by these receptors is the first step in the development of new diagnostic tools and treatment for the associated diseases.

Distinct structural abnormalities of genes encoding G protein-coupled receptors have been implicated in a number of endocrine disorders, including reproductive disorders. Loss-of-function mutations of the G protein-coupled receptors are usually associated with hormone resistance conditions and, consequently with the phenotypes of complete or partial hormonal deficiency.3

In contrast, the gain-of-function mutations affecting these receptors are associated with hormonal hyperfunction conditions. The abnormal receptor activation determined by these mutations, most of them are missense mutations in the transmembrane domain, generally occur in the absence of the ligand (constitutively activation) and rarely in the presence of the cognate or noncognate ligand, characterizing the nonconstitutively and promiscuous receptor activation models, respectively.3,4

One of the great mysteries of human biology is what initiates puberty. Definitely, we currently know that gonadotropin-releasing hormone (GnRH) is a decapeptide central to the initiation of the reproductive hormone cascade. It is produced by hypothalamic neurons in a pulsatile manner and released into the hypophyseal portal circulation to stimulate the biosynthesis and secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The pituitary gonadotropins stimulate gonadal function, including gametogenesis and steroid hormone synthesis. However, little is known about the precise mechanisms underlying the maturation and function of GnRH neurons and the regulation of GnRH secretion.5 The episodic release of GnRH seems to be modulated by excitatory and inhibitory signals transmitted by neurohormones and neurotransmitters acting at the level of the hypothalamus. The complex composed of a G protein-coupled receptor, GPR54, and its endogenous ligand, kisspeptin, was recently described as a new excitatory neuroregulator system for the secretion of GnRH. In the last 6 years, several loss-of-function point mutations and deletions of the human GPR54 were identified in familial or sporadic isolated hypogonadotropic hypogonadism without olfactory abnormalities.6-11 In addition, a unique gain-of-function missense mutation in the carboxy-terminal tail of the GPR54 was identified in a girl with idiopathic central precocious puberty.12 Taken together, these findings have established the essential role of the GPR54 as a genetic determinant and irrefutable gatekeeper of normal reproductive function.13

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