A Biological Role for the Gonadotrophin‐Releasing Hormone (GnRH) Metabolite, GnRH‐(1‐5)

Abstract

Gonadotrophin‐releasing hormone (GnRH) was first isolated in the mammal and shown to be the primary regulator of the reproductive system through its initiation of pituitary gonadotrophin release. Subsequent to its discovery, this form of GnRH has been shown to be one of many structural variants found in the brain and peripheral tissues. Accordingly, the original form first discovered and cloned in the mammal is commonly referred to as GnRH‐I. In addition to the complex regulation of GnRH‐I synthesis, release and function, further evidence suggests that the processing of GnRH‐I produces yet another layer of complexity in its activity. GnRH‐I is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15), which cleaves the hormone at the covalent bond between the fifth and sixth residue of the decapeptide (Tyr5‐Gly6) to form GnRH‐(1‐5). It was previously thought that the cleavage of GnRH‐I by EP24.15 represents the initiation of its degradation. Here, we review the evidence for the involvement of GnRH‐(1‐5), the metabolite of GnRH‐I, in the regulation of GnRH‐I synthesis, secretion and facilitation of reproductive behaviour.

Neuropeptidase activity is down-regulated by estradiol in steroid-sensitive regions of the hypothalamus in female mice

“…Although PEP and TOP cooperate in hydrolysis of GnRH, and may function separately or in concert in protection from amyloid toxicity (Arif et al , 2009), each has distinct roles in other physiological processes in the brain as well as peripherally. TOP may act in brain to play a role in lordosis in female rodents (Wu et al , 2009), is implicated in neurotensin inactivation (Ferro et al , 2004), and its central role in bradykinin breakdown may extend to regulation of the cerebral microvasculature (Norman et al , 2001). PEP is thought to contribute to control of the cell cycle, learning, memory, mood, and several neurodegenerative diseases (Männisto et al , 2007; Rossner et al , 2005).…”

“…Furthermore, one of the products of TOP action on GnRH, GnRH1-5, is bioactive in promoting lordosis and in GnRH auto-regulation (reviewed in Roberts et al , 2007; Wu et al , 2009). The involvement of TOP and other neuropeptidases in breakdown of GnRH suggests that these enzymes may be another component of the hypothalamic-pituitary-gonadal HPG axis and therefore candidates for regulation by the end products, steroid hormones.…”

Thimet Oligopeptidase (EC 3.4.24.15) Key Functions Suggested by Knockout Mice Phenotype Characterization

“…Thimet oligopeptidase (EC 3.4.24.15; EP24.15, THOP1) was initially identified as a neuropeptide-inactivating enzyme in rat brain homogenates [1,2,3,4]. The majority of well-characterized THOP1 substrates are neuropeptides [5], including bradykinin [6,7], neurotensin [8,9,10], opioid peptides [1,11,12], angiotensin [13], and gonadotrophin-releasing hormone (GnRH) [14,15,16]. Studies have suggested that THOP1 could be secreted or associated to the external surface of the plasma membrane to function as a neuropeptide-degrading enzyme [17,18,19].…”