A novel mammalian receptor for the evolutionarily conserved type II GnRH

doi:10.1073/pnas.141048498

A novel mammalian receptor for the evolutionarily conserved type II GnRH

^*Medical Research Council Human Reproductive Sciences Unit, 37 Chalmers Street, Edinburgh EH3 9ET, Scotland; ^†Medical Research Council Molecular Reproductive Endocrinology Unit, Department of Medical Biochemistry, University of Cape Town Medical School, Observatory 7925, South Africa; ^¶ZymoGenetics Inc., 1201 Eastlake Avenue East, Seattle, WA 98102; and ^‖Wisconsin Regional Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, WI 53715-1229

Edited by S. M. McCann, Pennington Biomedical Research Center, Baton Rouge, LA, and approved May 14, 2001 (received for review January 30, 2001)

Abstract

Mammalian gonadotropin-releasing hormone (GnRH I: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) stimulates pituitary gonadotropin secretion, which in turn stimulates the gonads. Whereas a hypothalamic form of GnRH of variable structure (designated type I) had been shown to regulate reproduction through a cognate type I receptor, it has recently become evident that most vertebrates have one or two other forms of GnRH. One of these, designated type II GnRH (GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH₂), is conserved from fish to man and is widely distributed in the brain, suggesting important neuromodulatory functions such as regulating K⁺ channels and stimulating sexual arousal. We now report the cloning of a type II GnRH receptor from marmoset cDNA. The receptor has only 41% identity with the type I receptor and, unlike the type I receptor, has a carboxyl-terminal tail. The receptor is highly selective for GnRH II. As with the type I receptor, it couples to G_α _q/11 and also activates extracellular signal-regulated kinase (ERK1/2) but differs in activating p38 mitogen activated protein (MAP) kinase. The type II receptor is more widely distributed than the type I receptor and is expressed throughout the brain, including areas associated with sexual arousal, and in diverse non-neural and reproductive tissues, suggesting a variety of functions. Surprisingly, the type II receptor is expressed in the majority of gonadotropes. The presence of two GnRH receptors in gonadotropes, together with the differences in their signaling, suggests different roles in gonadotrope functioning.

Footnotes

↵ ‡ R.M. and S.L. contributed equally to this work.
↵ § To whom reprint requests should be addressed. E-mail: r.millar{at}hrsu.mrc.ac.uk.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF368286).
↵ ** Muske, L. E., King, J. A., O'Connell, B. G., Moore, F. L. & Millar, R. P. (1995) Soc. Neurosci. Abstr. 21, 100.
Abbreviations:

GnRH,

gonadotropin-releasing hormone;

FSH,

follicle-stimulating hormone;

LH,

luteinizing hormone;

MAP kinase,

mitogen-activated protein kinase;

ERK,

extracellular signal-regulated kinase;

JNK,

c-Jun N-terminal kinase;

TMD,

transmembrane domain;

EC,

extracellular loop domain;

RACE,

rapid amplification of cDNA ends;

EST,

expressed sequence tag