title: Relaxin-3 stimulates the neuro-endocrine stress axis via corticotrophin-releasing hormone.
abstract: Relaxin-3 is a member of the insulin superfamily. It is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to RXFP1 and RXFP3. RXFP3 is expressed within the hypothalamic paraventricular nucleus (PVN), an area central to the stress response. The physiological function of relaxin-3 is unknown but previous work suggests a role in appetite control, stimulation of the hypothalamic-pituitary-gonadal axis and stress. Central administration of relaxin-3 induces c-fos expression in the PVN and increases plasma ACTH levels in rats. The aim of this study was to investigate the effect of central administration of human relaxin-3 (H3) on the hypothalamic-pituitary-adrenal (HPA) axis in male rodents in vivo and in vitro. Intracerebroventricular (i.c.v) administration of H3 (5 nmol) significantly increased plasma corticosterone at 30 min following injection compared with vehicle. Intra-PVN administration of H3 (1.8-1620 pmol) significantly increased plasma ACTH at 1620 pmol H3 and corticosterone at 180-1620 pmol H3 at 30 min following injection compared with vehicle. The stress hormone prolactin was also significantly raised at 15 min post-injection compared with vehicle. Treatment of hypothalamic explants with H3 (10-1000 nM) stimulated the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), but H3 had no effect on the release of ACTH from in vitro pituitary fragments. These results suggest that relaxin-3 may regulate the HPA axis, via hypothalamic CRH and AVP neurons. Relaxin-3 may act as a central signal linking nutritional status, reproductive function and stress.
authors.affiliation: Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, London Section of Investigative Medicine, Department of Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Campus, Du Cane Road, London W12 ONN, UK Molecular Genetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: McGowan
authors.forename: J S
authors.initials: JS
authors.lastname: Minnion
authors.forename: K G
authors.initials: KG
authors.lastname: Murphy
authors.forename: D
authors.initials: D
authors.lastname: Roy
authors.forename: S A
authors.initials: SA
authors.lastname: Stanley
authors.forename: W S
authors.initials: WS
authors.lastname: Dhillo
authors.forename: J V
authors.initials: JV
authors.lastname: Gardiner
authors.forename: M A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: S R
authors.initials: SR
authors.lastname: Bloom
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012065:Relaxin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D009419:Nerve Tissue Proteins; C466742:RLN3 protein, rat; D000324:Adrenocorticotropic Hormone; D012065:Relaxin; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: ACTH; RXFP1; RXFP3; corticosterone; paraventricular nucleus; relaxin-3