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Potent Action of RFamide-Related Peptide-3 on Pituitary Gonadotropes Indicative of a Hypophysiotropic Role in the Negative Regulation of Gonadotropin Secretion

Department of Physiology (I.J.C., I.P.S., Y.Q,. J.T.S., H.C.P., J.I., Q.L., A.T.), Monash University, Victoria 3800, Australia; Department of Integrative Biology and Helen Wills Neuroscience Institute (T.U., G.E.B.), University of California at Berkeley, Berkeley, California 94720-3140; Medical Research Council Human Reproductive Sciences Unit (K.M., A.J.P., R.P.M.), Centre for Reproductive Biology, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom; Department of Biology (K.T.), Waseda University, Shinjuku-ku, Tokyo 169-8050, Japan; and Department of Medical Biochemistry (R.P.M.), University of Cape Town, Cape Town 7925, South Africa

Address all correspondence and requests for reprints to: Professor Iain Clarke, Department Physiology, Building 13F, Monash University, Clayton Victoria 3800, Australia. E-mail: iain.clarke{at}med.monash.edu.au.

We identified a gene in the ovine hypothalamus encoding for RFamide-related peptide-3 (RFRP-3), and tested the hypothesis that this system produces a hypophysiotropic hormone that inhibits the function of pituitary gonadotropes. The RFRP-3 gene encodes for a peptide that appears identical to human RFRP-3 homolog. Using an antiserum raised against RFRP-3, cells were localized to the dorsomedial hypothalamic nucleus/paraventricular nucleus of the ovine brain and shown to project to the neurosecretory zone of the ovine median eminence, predicating a role for this peptide in the regulation of anterior pituitary gland function. Ovine RFRP-3 peptide was tested for biological activity in vitro and in vivo, and was shown to reduce LH and FSH secretion in a specific manner. RFRP-3 potently inhibited GnRH-stimulated mobilization of intracellular calcium in gonadotropes. These data indicate that RFRP-3 is a specific and potent mammalian gonadotropin-inhibiting hormone, and that it acts upon pituitary gonadotropes to reduce GnRH-stimulated gonadotropin secretion.

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