A novel mammalian receptor for the evolutionarily conserved type II GnRH.
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(alpha)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.
Millar
R
R
Medical Research Council Human Reproductive Sciences Unit, Edinburgh EH3 9ET, Scotland. r.millar@hrsu.mrc.ac.uk
Lowe
S
S
Conklin
D
D
Pawson
A
A
Maudsley
S
S
Troskie
B
B
Ott
T
T
Millar
M
M
Lincoln
G
G
Sellar
R
R
Faurholm
B
B
Scobie
G
G
Kuestner
R
R
Terasawa
E
E
Katz
A
A
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002144:Callithrix; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D020224:Expressed Sequence Tags; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000502:physiology*; D000882:Haplorhini; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D009420:Nervous System / Q000196:embryology; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D011966:Receptors, LHRH / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012098:Reproduction / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D012726:Sexual Behavior, Animal / Q000502:physiology; D012756:Sheep; D015398:Signal Transduction; D013045:Species Specificity
C427484:GNRHR2 protein, human; D007295:Inositol Phosphates; D009419:Nerve Tissue Proteins; D011966:Receptors, LHRH; D011993:Recombinant Fusion Proteins; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C047717:LHRH, His(5)-Trp(7)-Tyr(8)-