Regulation of GPR54 Signaling by GRK2 and β-Arrestin

Pampillo, Macarena; Camuso, N.; Taylor, Jay E.; Szereszewski, Jacob M.; Ahow, Maryse R.; Zajac, Mateusz; Millar, Robert P.; Bhattacharya, Moshmi; Babwah, Andy V.

doi:10.1210/me.2009-0013

Cited by 95 publications

(127 citation statements)

References 53 publications

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“…DAG then activates protein kinase C. Mitogen-activated protein kinases (MAPKs) are phosphorylated, thereby activating β-arrestin and inositol-1,4,5-triphosphate. Consequently, intracellular calcium is released, depolarising the neuron (3,4,(11)(12)(13)(14)(15) (Fig. 2).…”

Section: Intracellular Signalling Mechanismsmentioning

confidence: 99%

Kisspeptin signalling and its roles in humans

Tng

2015

smedj

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Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors are expressed by neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus. Oestrogen mediates negative feedback of gonadotrophin-releasing hormone secretion via the arcuate nucleus. Conversely, it exerts positive feedback via the anteroventral periventricular nucleus. The sexual dimorphism of these nuclei accounts for the differential behaviour of the hypothalamic-pituitary-gonadal axis between genders. Kisspeptins are essential for reproductive function. Puberty is regulated by the maturation of kisspeptin neurons and by interactions between kisspeptins and leptin. Hence, kisspeptins have potential diagnostic and therapeutic applications. Kisspeptin agonists may be used to localise lesions in cases of hypothalamic-pituitary-gonadal axis dysfunction and evaluate the gonadotrophic potential of subfertile individuals. Kisspeptin antagonists may be useful as contraceptives in women, through the prevention of premature luteinisation during in vitro fertilisation, and in the treatment of sex steroid-dependent diseases and metastatic cancers.

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Section: Intracellular Signalling Mechanismsmentioning

confidence: 99%

Kisspeptin signalling and its roles in humans

Tng

2015

smedj

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“…This observation indicates that the kisspeptin receptor is desensitized by continuous kisspeptin treatment. The mechanisms of kisspeptin receptor desensitization are not clear but seem to involve G-protein-coupled receptor (GPCR) kinase 2 (Pampillo et al 2009). In sheep, concentrations of LH also decrease during continuous infusion of kisspeptin (Messager et al 2005); however, low doses of kisspeptin infused constantly increase concentrations of E 2 in circulation and stimulate ovulation in anestrous ewes , Sebert et al 2010.…”

Section: Control (Nz5)mentioning

confidence: 99%

Kisspeptin activates the hypothalamic–adenohypophyseal–gonadal axis in prepubertal ewe lambs

Redmond¹,

Macedo²,

Velez³

et al. 2011

Reproduction

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The onset of puberty in mammals involves an increase in the pulsatile release of GNRH and LH. The KISS1 gene is essential for pubertal development, and its product, kisspeptin, stimulates the release of LH. The objective of this study was to determine the effects of kisspeptin in the hypothalamic-adenohypophyseal-gonadal axis of prepubertal ewe lambs. Ewe lambs (28 weeks of age) were treated intravenously with saline (control, nZ6) or kisspeptin (20 mg kisspeptin; nZ6) every hour for 24 h. Kisspeptin stimulated pulse-like release of LH within 15 min following injections, and increased the frequency and amplitude of LH pulses, and mean circulating concentrations of LH and estradiol. A surge-like release of LH was observed in four kisspeptin-treated lambs beginning 17 h after the onset of treatment, and all four lambs had elevated circulating concentrations of progesterone within 5 days post-treatment. However, circulating concentrations of progesterone decreased within 2 days after the initial rise in three of the four ewe lambs, indicating that induced luteal activity was of short duration. The proportion of lambs that were pubertal (defined by circulating concentrations of progesterone above 1 ng/ml for at least 7 days) by 35 weeks of age (8/11) and the mean age at puberty (32G1 weeks) for those reaching puberty within the experimental period did not differ between treatments. Results support a role for kisspeptin in the activation of the hypothalamic-adenohypophyseal axis leading to the onset of puberty in ewe lambs.

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“…Furthermore, high levels of kisspeptins have been found in pregnant women as compared to non-pregnant women, suggesting kisspeptin is placenta derived [167]. The levels rise substantially as the pregnancy progresses and stay high until parturition [167], which has been suggested to play an important role in negatively modulating the trophoblastic invasion in later pregnancy [106,[172][173][174]. Additionally, low levels of kisspeptins have been found to be associated with gestational diabetes mellitus as they stimulate glucosedependent insulin secretion [175,176].…”

Section: Prace Poglądowementioning

confidence: 99%

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

Javed

Qamar

Sathyapalan

2015

Endokrynologia Polska

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The discovery of kisspeptins in the recent past remoulded current understanding of the neuroendocrine axis relating to the regulation of human puberty and reproduction. Kisspeptins have been recognised to act upstream of GnRH and have been shown to play a vital role in the control of the hypothalamic-pituitary-gonadal axis via regulation of gonadotrophin secretion, onset of puberty, and control of fertility. KNDy (kisspeptin/neurokinin-B/dynorphin) neurons have been suggested to modulate GnRH pulsatile secretion, which is required to support reproductive function in both sexes. They have also been involved in mediating both positive and negative sex steroid feedback signals to GnRH neurons and serve as a vital connection between reproduction and metabolic status of the body. When kisspeptin is administered to healthy humans, and in patients with reproductive disorders, it strongly and directly stimulates GnRH and subsequent LH secretion and enhances LH pulse frequency. These observations suggest that kisspeptins are a potential novel therapeutic approach for treating disorders with either pathologically reduced or augmented gonadotrophins pulsatile secretion and is currently a focus of translational research. Kisspeptins have also been identified in several peripheral reproductive organs, indicating their role in modulation of ovarian function, embryo implantation, and placentation, but a great deal of work remains to be done to explore further in this regard, and the evidence is only available from studies done on animal models. In this review we will mainly focus on current available evidence related to the role of kisspeptins in controlling GnRH pulse frequency, specifically their role in puberty, fertility, and reproduction. We will also be appraising other factors that regulate the kiSS1/Kisspeptin/GPR-54 system. StreszczenieOdkrycie kisspeptyn, które miało miejsce całkiem niedawno, odmieniło obecne rozumienie osi neuroendokrynnej, związanej z regulacją okresu dojrzewania i rozrodu. Odkryto, że kisspeptyny działają przed GnRH i odgrywają istotną rolę w kontroli osi podwzgórze-przysadka-nadnercza poprzez regulację wydzielania gonadotropiny, rozpoczęcia okresu dojrzewania oraz kontroli płodności. Zasugerowano, że komórki KNDy (kisspeptyna/neurokinina-B/dynorfina) modulują pulsacyjne uwalnianie GnRH, wymagane, aby wspomagać funkcję rozrodczą u obu płci. Komórki te są również zaangażowane w przekazywanie zarówno pozytywnych, jak i negatywnych sygnałów hormonów płciowych do neuronów GnRH, a także stanowią kluczowe połączenie między reprodukcją i stanem metabolicznym ciała. Kiedy kisspeptyna jest podawana jednostkom zdrowym i pacjentom z zaburzeniami płodności, silnie i bezpośrednio stymuluje GnPH i dalsze uwalnianie LH oraz poprawia częstotliwość impulsów LH. Obserwacje te przedstawiają kisspeptyny jako nowe potencjalne terapeutyczne podejście w leczeniu zaburzeń patologicznie obniżonego lub zwiększonego pulsacyjnego uwalniania gonadotropin i obecnie stanowi główny punkt zainteresowania badań przekładaj...

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Regulation of GPR54 Signaling by GRK2 and β-Arrestin

Cited by 95 publications

References 53 publications

Kisspeptin signalling and its roles in humans

Kisspeptin signalling and its roles in humans

Kisspeptin activates the hypothalamic–adenohypophyseal–gonadal axis in prepubertal ewe lambs

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

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