ECE2016 Guided Posters Neuroendocrinology (10 abstracts)
Hypothalamic GRK2, via GPR54, modulates puberty onset
Ma Soledad Avendaño 1, , Francisco Ruiz-Pino 1, , Ma Jesús Vázquez 1, , Inmaculada Velasco 1, , Violeta Heras 1, , Encarni Torres 1, , Juan Manuel Castellano 1, , Juan Roa 1, , Leonor Pinilla 1, & Manuel Tena-Sempere 1,
1Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/ HURS), Cordoba, Andalusia, Spain; 2CIBER Fisio-patología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004, Cordoba, Andalusia, Spain.
The G protein-coupled receptor (GPCR) kinase 2, GRK2, is a ubiquitous serine/threonine protein kinase that is able to phosphorylate and desensitize the active form of several GPCR. Compelling, as yet limited, evidence from in vitro studies have suggested a potential role of GRK2 in mediating desensitization of Gpr54, the canonical receptor for kisspeptins that is abundantly expressed in GnRH neurons. Yet, although kisspeptins have been universally recognized as essential regulators of puberty and fertility, the physiological role of GRK2 in modulating kisspeptin signalling in vivo remains completely unexplored. We report herein a series of expression and functional analyses addressing the putative role of central (hypothalamic) GRK2 in the regulation of puberty, as major developmental event under the control of kisspeptins (and related factors). Expression analyses revealed a gradual increase of GRK2 mRNA and protein levels in the hypothalamus during postnatal maturation, especially in the preoptic area, where most GnRH neurons reside. Of note, models of delayed puberty, due to postnatal under-nutrition or manipulation of neonatal sex steroid milieu, displayed an exaggerated increase of hypothalamic GRK2 expression. In addition, intracerebro-ventricular (icv) injection of a GRK2 inhibitor enhanced LH and FSH secretion in response to acute kisspeptin-10, but not to NKB, administration. Furthermore, chronic icv administration of a GRK2 inhibitor caused an advancement of puberty onset, evidenced by earlier vaginal opening and first ovulation, together with increased ovarian and uterus weights. Alike, central GRK2 inhibition partially rescued the delay in puberty onset caused by postnatal under-nutrition. Altogether, our results demonstrate that GRK2 regulates hypothalamic Gpr54 signalling in vivo and provide conclusive evidence for a crucial role of GRK2 in the fine tuning of pubertal timing, likely via modulation of kisspeptin actions, in normal and metabolically or hormonally compromised conditions.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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