Gonadotropin-Releasing Hormone II: Is this Neuropeptide Important for Mammalian Reproduction?
Since GnRH was first isolated from the pig brain more than three decades ago, an additional 16 novel GnRH structural variants, all of which are composed of 10 amino acids, have been identified in the animal kingdom (1, 2, 3, 4, 5, 6). Among them, chicken GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly·NH2), the second form isolated from the chicken brain, is the evolutionarily conserved form, as it was found in the brains of jawed fish to humans (1). After the isolation of this form from the human brain recently (7), it has been renamed GnRH II, and pGlu-His-Trp-Ser-Try-Gly-Leu-Arg-Pro-Gly·NH2 has been renamed GnRH I (7). Whereas perikarya of GnRH I are distributed widely in the preoptic area and hypothalamus with their fibers converging in the median eminence and pituitary stalk, perikarya of GnRH II are primarily present in the midbrain and extrahypothalamic regions (8, 9). Hypophysiotropic GnRH in all mammals, except for in guinea pigs, is GnRH I, whereas the molecular structure of hypophysiotropic GnRH among nonmammalian species is quite diverse (1).
Two seven-transmembrane G protein-coupled receptors, each having a specificity for GnRH I and GnRH II as a ligand, have been cloned in various animals including fishes, and designated as GnRH receptor type I and type II, respectively (10, 11, 12). Whereas the type II receptors have a C-terminal cytoplasmic tail by which GnRH internalization and desensitization of receptors are controlled (11, 12), the type I receptors do not have the C-terminal domain (10).9%6, http://www.100md.com
There is a possibility that GnRH II plays a role in the control of gonadotropin secretion, perhaps preferentially stimulating FSH secretion. Large numbers of gonadotropes express not only receptors for GnRH I, but also for GnRH II (11). A few GnRH neurons were found in the pituitary stalk and GnRH II stimulates LH as powerfully as GnRH I (8). GnRH II also stimulates 3H-inositol phosphate production in the anterior pituitary (11, 13). However, the differential role of GnRH II and GnRH I in control of gonadotropin secretion requires further investigation and evidence for GnRH II release in the portal circulation has yet to be demonstrated.
Then, what is the function of GnRH II in the mammalian brain? The distribution pattern of GnRH II primarily in the midbrain and extrahypothalamic regions may be indicative for a neurotransmitter involved in sexual behavior, rather than a hypophysiotropic hormone. In the amphibian sympathetic ganglion, GnRH II inhibits M current through K+ channels (14) and administration of GnRH II, but not chicken GnRH I (GnRH I for birds), to female sparrows facilitated solicitation behavior in response to male song (15). GnRH I was shown to stimulate lordosis behavior in female rats three decades ago (16, 17). Findings shown in female musk shrews (Suncus murinus) by Emilie Rissman’s laboratory (published in this issue; see Ref. 18) clearly demonstrate that GnRH II is a neurotransmitter/modulator for reproductive behavior.!k, 百拇医药
In the article, Rissman and colleagues used food-restricted female musk shrews because in previous studies sexual behavior was inhibited by food restriction (60% of normal feeding for 2 d) and GnRH II was not effective in ad libitum- fed females (19). In the present article (18), the authors clearly demonstrated that administration of GnRH II into the lateral ventricle of food-restricted female musk shrews significantly shortened the latency to sexual behavior and increased the rate of females receiving mounts from males. A similar administration of GnRH I was not effective. The authors further demonstrated that 1) the number of immunoreactive GnRH II cells in the midbrain and immunoreactive fiber density in the median eminence of food-restricted females were significantly larger than those in ad libitum-fed females, presumably due to inhibition of GnRH II release; and 2) the presence of immunopositive type II GnRH receptors was confirmed in the areas that were involved in sexual behavior, such as preoptic area, ventromedial nucleus, arcuate nucleus, pituitary stalk, habenula, and cingulate cortex. Because GnRH II was not effective in ad libitum-fed females, the authors conclude that the importance of GnRH II may become apparent in a subliminal condition, such as a nutritionally challenged situation.
Until recently, it has been believed that GnRH I is a single molecule controlling synthesis and release of gonadotropins, and sexual behavior, hence reproductive function. The discovery of Temple et al. (18) is very important because it shows that GnRH II in the brain also plays a role in controlling reproductive function in mammalian species. At this point, it is unclear whether the GnRH II system is a redundant mechanism for the reproductive success residual from animal evolution or a fail-safe mechanism for reproductive success, hence the species preservation, under conditions such as unpredictable nutritional resources. It is also unclear whether a similar mechanism can be found in primates. Nonetheless, it is time to honor comparative neuroendocrinologists, because this new concept could not have emerged without the data from many different animals, especially from lower vertebrates.#v;|f, 百拇医药
Received November 5, 2002.#v;|f, 百拇医药
Accepted for publication November 5, 2002.
Referencesao, 百拇医药
Sherwood NM, Lovejoy DA, Coe IR 1993 Origin of mammalian gonadotropin-releasing hormones. Endocr Rev 14:241–254ao, 百拇医药
Sherwood NM, von Schalburg K, Lescheid DW 1997 Origin and evolution of GnRH in vertebrates and invertebrates. In: Parher IS, Sakuma Y, eds. GnRH neurons: gene to behavior. Tokyo: Brain Shuppan; 3–26ao, 百拇医药
King JA, Millar RP 1997 Coordinated evolution of GnRHs and their receptors. In: Parher IS, Sakuma Y, eds. GnRH neurons: gene to behavior. Tokyo: Brain Shuppan; 57-77ao, 百拇医药
Okubo K, Amano M, Yoshiura Y, Suetake H, Aida K 2000 A novel form of gonadotropin-releasing hormone in the medaka, Oryzias latipies. Biochem Biophys Res Commun 276:298–303ao, 百拇医药
Iwakoshi E, Takuwa-Kuroda K, Fujisawa Y, Hisada M, Ukena K, Tsutsui K, Minakata H 2002 Isolation and characterization of a GnRH-like peptide from octopus vulgaris. Biochem Biophys Res Commun 291:1187–1193ao, 百拇医药
Adams BA, Vickers ED, Warby C, Park M, Fisher WH, Craig AG, Rivier JE, Sherwood NM 2002 Three forms of gonadotropin-releasing hormone, including a novel form, in a basal salmonid, Coregonus clupeaformis. Biol Reprod 67:232–239
White RB, Eisen JA, Kasten TL, Fernald RD 1998 Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci USA 95:305–309cm, 百拇医药
Lescheid DW, Terasawa E, Abler LA, Urbanski HF, Warby CM, Millar RP, Sherwood NM 1997 A second form of gonadotropin-releasing hormone (GnRH) with characteristics of chicken GnRH II is present in the primate brain. Endocrinology 138:5618–5629cm, 百拇医药
Urbanski HF, White RB, Fernald RD, Kohama SG, Garyfallou VT, Densmore VS 1999 Regional expression of mRNA endcoding a second form of gonadotropin-releasing hormone in the macaque brain. Endocrinology 140:1945–1948cm, 百拇医药
Sealfon SC, Weinstein H, Millar RP 1997 Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr Rev 18:180–205cm, 百拇医药
Millar R, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie B, Ott T, Millar M, Lincoln G, Sellar R, Faurholm B, Scobie G, Kuestner R, Terasawa E, Katz A 2001 A novel mammalian receptor for the evolutionarily conserved type II GnRH receptor. Proc Natl Acad Sci USA 98:9636–9641
Neill JD, Duck LW, Sellers JC, Musgrove LC 2001 A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun 282:1012–1018k, 百拇医药
Neill JD 2002 Minireview: GnRH and GnRH receptor genes in the human genome. Endocrinology 143:737–743k, 百拇医药
Bosma MM, Bernheim L, Leibowitz MD, Pfaffinger PJ, Hille B 1990 Modulation of M current in frog sympathetic ganglion cells. In: Nathanson NM, Harden TK, eds. G protein and signal transduction. New York: The Rockefeller University Press; 43–59k, 百拇医药
Maney DL, Richardson RD, Wingfield JC 1997 Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow. Horm Behav 32:11–18k, 百拇医药
Moss RL, McCann SM 1973 induction of mating behavior in rats by luteinizing hormone-releasing factor. Science 181:177–179k, 百拇医药
Pfaff DW 1973 Luteinizing hormone-releasing factor potentiates lordosis behavior in hypophysectomized ovariectomized female rats. Science 182:1148–1149k, 百拇医药
Temple JL, Millar RP, Rissman EF 2003 An evolutionarily conserved form of gonadotropin-releasing hormone coordinates energy and reproductive behavior. Endocrinology 144:13–19k, 百拇医药
Temple JL, Rissman EF 2000 Brief re-feeding restores reproductive readiness in food restricted female musk shrews. Horm Behav 38:21–28(Ei Terasawa)
Two seven-transmembrane G protein-coupled receptors, each having a specificity for GnRH I and GnRH II as a ligand, have been cloned in various animals including fishes, and designated as GnRH receptor type I and type II, respectively (10, 11, 12). Whereas the type II receptors have a C-terminal cytoplasmic tail by which GnRH internalization and desensitization of receptors are controlled (11, 12), the type I receptors do not have the C-terminal domain (10).9%6, http://www.100md.com
There is a possibility that GnRH II plays a role in the control of gonadotropin secretion, perhaps preferentially stimulating FSH secretion. Large numbers of gonadotropes express not only receptors for GnRH I, but also for GnRH II (11). A few GnRH neurons were found in the pituitary stalk and GnRH II stimulates LH as powerfully as GnRH I (8). GnRH II also stimulates 3H-inositol phosphate production in the anterior pituitary (11, 13). However, the differential role of GnRH II and GnRH I in control of gonadotropin secretion requires further investigation and evidence for GnRH II release in the portal circulation has yet to be demonstrated.
Then, what is the function of GnRH II in the mammalian brain? The distribution pattern of GnRH II primarily in the midbrain and extrahypothalamic regions may be indicative for a neurotransmitter involved in sexual behavior, rather than a hypophysiotropic hormone. In the amphibian sympathetic ganglion, GnRH II inhibits M current through K+ channels (14) and administration of GnRH II, but not chicken GnRH I (GnRH I for birds), to female sparrows facilitated solicitation behavior in response to male song (15). GnRH I was shown to stimulate lordosis behavior in female rats three decades ago (16, 17). Findings shown in female musk shrews (Suncus murinus) by Emilie Rissman’s laboratory (published in this issue; see Ref. 18) clearly demonstrate that GnRH II is a neurotransmitter/modulator for reproductive behavior.!k, 百拇医药
In the article, Rissman and colleagues used food-restricted female musk shrews because in previous studies sexual behavior was inhibited by food restriction (60% of normal feeding for 2 d) and GnRH II was not effective in ad libitum- fed females (19). In the present article (18), the authors clearly demonstrated that administration of GnRH II into the lateral ventricle of food-restricted female musk shrews significantly shortened the latency to sexual behavior and increased the rate of females receiving mounts from males. A similar administration of GnRH I was not effective. The authors further demonstrated that 1) the number of immunoreactive GnRH II cells in the midbrain and immunoreactive fiber density in the median eminence of food-restricted females were significantly larger than those in ad libitum-fed females, presumably due to inhibition of GnRH II release; and 2) the presence of immunopositive type II GnRH receptors was confirmed in the areas that were involved in sexual behavior, such as preoptic area, ventromedial nucleus, arcuate nucleus, pituitary stalk, habenula, and cingulate cortex. Because GnRH II was not effective in ad libitum-fed females, the authors conclude that the importance of GnRH II may become apparent in a subliminal condition, such as a nutritionally challenged situation.
Until recently, it has been believed that GnRH I is a single molecule controlling synthesis and release of gonadotropins, and sexual behavior, hence reproductive function. The discovery of Temple et al. (18) is very important because it shows that GnRH II in the brain also plays a role in controlling reproductive function in mammalian species. At this point, it is unclear whether the GnRH II system is a redundant mechanism for the reproductive success residual from animal evolution or a fail-safe mechanism for reproductive success, hence the species preservation, under conditions such as unpredictable nutritional resources. It is also unclear whether a similar mechanism can be found in primates. Nonetheless, it is time to honor comparative neuroendocrinologists, because this new concept could not have emerged without the data from many different animals, especially from lower vertebrates.#v;|f, 百拇医药
Received November 5, 2002.#v;|f, 百拇医药
Accepted for publication November 5, 2002.
Referencesao, 百拇医药
Sherwood NM, Lovejoy DA, Coe IR 1993 Origin of mammalian gonadotropin-releasing hormones. Endocr Rev 14:241–254ao, 百拇医药
Sherwood NM, von Schalburg K, Lescheid DW 1997 Origin and evolution of GnRH in vertebrates and invertebrates. In: Parher IS, Sakuma Y, eds. GnRH neurons: gene to behavior. Tokyo: Brain Shuppan; 3–26ao, 百拇医药
King JA, Millar RP 1997 Coordinated evolution of GnRHs and their receptors. In: Parher IS, Sakuma Y, eds. GnRH neurons: gene to behavior. Tokyo: Brain Shuppan; 57-77ao, 百拇医药
Okubo K, Amano M, Yoshiura Y, Suetake H, Aida K 2000 A novel form of gonadotropin-releasing hormone in the medaka, Oryzias latipies. Biochem Biophys Res Commun 276:298–303ao, 百拇医药
Iwakoshi E, Takuwa-Kuroda K, Fujisawa Y, Hisada M, Ukena K, Tsutsui K, Minakata H 2002 Isolation and characterization of a GnRH-like peptide from octopus vulgaris. Biochem Biophys Res Commun 291:1187–1193ao, 百拇医药
Adams BA, Vickers ED, Warby C, Park M, Fisher WH, Craig AG, Rivier JE, Sherwood NM 2002 Three forms of gonadotropin-releasing hormone, including a novel form, in a basal salmonid, Coregonus clupeaformis. Biol Reprod 67:232–239
White RB, Eisen JA, Kasten TL, Fernald RD 1998 Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci USA 95:305–309cm, 百拇医药
Lescheid DW, Terasawa E, Abler LA, Urbanski HF, Warby CM, Millar RP, Sherwood NM 1997 A second form of gonadotropin-releasing hormone (GnRH) with characteristics of chicken GnRH II is present in the primate brain. Endocrinology 138:5618–5629cm, 百拇医药
Urbanski HF, White RB, Fernald RD, Kohama SG, Garyfallou VT, Densmore VS 1999 Regional expression of mRNA endcoding a second form of gonadotropin-releasing hormone in the macaque brain. Endocrinology 140:1945–1948cm, 百拇医药
Sealfon SC, Weinstein H, Millar RP 1997 Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr Rev 18:180–205cm, 百拇医药
Millar R, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie B, Ott T, Millar M, Lincoln G, Sellar R, Faurholm B, Scobie G, Kuestner R, Terasawa E, Katz A 2001 A novel mammalian receptor for the evolutionarily conserved type II GnRH receptor. Proc Natl Acad Sci USA 98:9636–9641
Neill JD, Duck LW, Sellers JC, Musgrove LC 2001 A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun 282:1012–1018k, 百拇医药
Neill JD 2002 Minireview: GnRH and GnRH receptor genes in the human genome. Endocrinology 143:737–743k, 百拇医药
Bosma MM, Bernheim L, Leibowitz MD, Pfaffinger PJ, Hille B 1990 Modulation of M current in frog sympathetic ganglion cells. In: Nathanson NM, Harden TK, eds. G protein and signal transduction. New York: The Rockefeller University Press; 43–59k, 百拇医药
Maney DL, Richardson RD, Wingfield JC 1997 Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow. Horm Behav 32:11–18k, 百拇医药
Moss RL, McCann SM 1973 induction of mating behavior in rats by luteinizing hormone-releasing factor. Science 181:177–179k, 百拇医药
Pfaff DW 1973 Luteinizing hormone-releasing factor potentiates lordosis behavior in hypophysectomized ovariectomized female rats. Science 182:1148–1149k, 百拇医药
Temple JL, Millar RP, Rissman EF 2003 An evolutionarily conserved form of gonadotropin-releasing hormone coordinates energy and reproductive behavior. Endocrinology 144:13–19k, 百拇医药
Temple JL, Rissman EF 2000 Brief re-feeding restores reproductive readiness in food restricted female musk shrews. Horm Behav 38:21–28(Ei Terasawa)