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Wisconsin National Primate Research Center, Department of Pediatrics and Center for Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin 53715-1299
Address all correspondence and requests for reprints to: Ei Terasawa, Ph.D., Wisconsin National Primate Research Center, 1223 Capitol Court, Madison, Wisconsin 53715-1299. E-mail: terasawa{at}primate.wisc.edu. Please reference publication no. 42-011 of The Wisconsin National Primate Center with any requests for reprints.
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).
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.
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.
Received November 5, 2002.
Accepted for publication November 5, 2002.
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