GnRH II and type II GnRH receptors

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Abstract

Hypothalamic gonadotrophin-releasing hormone (GnRH I), which is of a variable structure in vertebrates, is the central regulator of the reproductive system through its stimulation of gonadotrophin release from the pituitary. A second form of GnRH (GnRH II) is ubiquitous and conserved in structure from fish to humans, suggesting that it has important functions and a discriminating receptor that selects against structural change. GnRH II is distributed in discrete regions of the central and peripheral nervous systems and in nonneural tissues. The cognate receptor for GnRH II has recently been cloned from amphibians and mammals. It is highly selective for GnRH II, has a similar distribution to GnRH II in the nervous system and, notably, in areas associated with sexual behaviour. It is also found in reproductive tissues. An established function of GnRH II is in the inhibition of M currents (K+ channels) through the GnRH II receptor in the amphibian sympathetic ganglion, and it might act through this mechanism as a neuromodulator in the central nervous system. The conservation of structure over 500 million years and the wide tissue distribution of GnRH II suggest that it has a variety of reproductive and nonreproductive functions and will be a productive area of research.

Section snippets

GnRH II is an ancient and structurally conserved peptide

GnRH II is present unchanged in numerous species representing all the major vertebrate classes 5, 6. Only in the primitive jawless fish (agnathans) is there no evidence of GnRH II. Why should the GnRH II structure have been totally conserved whereas forms of GnRH I have undergone considerable structural change? One possibility is that GnRH II binds more than one GnRH receptor subtype and that the structural requirements of these receptors are different, thereby ensuring conservation of all the

GnRH II is widely distributed in the nervous system and periphery

The distinguishing feature of GnRH II is its wide distribution in extrahypothalamic regions of the brain when compared with GnRH I. Although, similar to GnRH I, it does occur in preoptic and medio-basal hypothalamic areas, it is characterized especially by its occurrence in the midbrain and limbic structures of nonmammals and mammals, where it is thought to be involved in reproductive behaviour 5, 7, 8, 13. In humans and primates, it is particularly abundant in the caudate nucleus, hippocampus

Cloning and primary structure of type II GnRH receptors

The presence of GnRH II in all vertebrates from jawed fish to humans indicates the probable existence of cognate type II GnRH receptors. This was supported by the presence of GnRH receptors in amphibian sympathetic ganglia that were selective for GnRH II [24].

Amplification of EC3 from genomic DNA from a range of vertebrate species revealed two distinct sequences of receptors representing the known type I receptors and novel type II receptors in an amphibian and a reptile [25]. These sequences

Ligand selectivity and intracellular signalling of type II GnRH receptors

The type II receptors are highly selective for GnRH II in receptor binding assays 10, 13 and in the stimulation of inositol phosphate intracellular messenger production (50–100-fold greater activity relative to mammalian GnRH I 10, 13, 14 (Table 1). Interestingly, some type I receptor GnRH antagonists behave as agonists at the type II receptor [13]. There are distinct differences in signalling by the two receptors (Table 1), which suggests that there might be different effects where the

Tissue distribution and expression of type II GnRH receptors

mRNA encoding the type II GnRH receptor is expressed in many parts of the human and marmoset brain, in addition to peripheral tissues (Table 2). A study using human multiple tissue expression arrays demonstrated expression in all human tissues [14], including those that were negative on northern blots [13]. These discrepancies might result from a higher nonspecific hybridization in mRNA dot assays. Immunocytochemical studies in the rhesus monkey gave similar results of receptor mRNA

Inhibition of K+ channels

The only established function of GnRH II is as an inhibitor of M currents (K+ channels) in amphibian sympathetic ganglia. GnRH II is more potent than GnRH I or GnRH III [32], is present in the sympathetic ganglion and preferentially binds to sympathetic ganglion receptors [24]. The cloning of the Xenopus sympathetic ganglion receptor (Blackman et al., unpublished) and demonstration that it is the homologue of the primate type II receptor is an important advance because it constitutes the only

Is there a functional human GnRH II receptor?

The first report of a GnRH II receptor homologue [11] came from a search of human expressed sequence tag (EST) databases using the EC3sequence of the putative reptile GnRH II receptor [25]. The ESTs could be assembled to produce a transcript encompassing the equivalent of exons 2 and 3 of the known type I receptor but exon 1 was not present in any of the EST transcripts [11]. Moreover, all transcripts had retained the intervening 400-bp intron and were in the antisense orientation [11]. It

Conclusions

The universal occurrence and conservation of structure of GnRH II in taxa representing 500 million years of evolution and its apparent role in gonadotrophin secretion, reproductive behaviour, and gonadal and sexual accessory organ function suggests that GnRH II might be the earliest evolved GnRH peptide with coordinated regulation of reproduction. The cloning of the type II GnRH receptor provides the opportunity to elucidate the effects and functions of the ligand in detail and for the

References (48)

  • J.C. Slimp

    Heterosexual, autosexual and social behavior of adult rhesus monkeys with medial preoptic-anterior hypothalamic lesions

    Brain Res.

    (1978)
  • K. Smalley et al.

    The involvement of p38 mitogen-activated protein kinase in the α-melanocyte stimulating hormone (α-MSH)-induced melanogenic and anti-proliferative effects in B16 murine melanoma cells

    FEBS Lett.

    (2000)
  • B. Faurholm

    The genes encoding for the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci

    Genomics

    (2001)
  • P.M. Conn et al.

    Gonadotropin-releasing hormone and its analogues

    Annu. Rev. Med.

    (1994)
  • E. Nieschlag

    Hormonal male contraception: a real chance?

  • H.M. Fraser

    GnRH analogues for contraception

    Br. Med. Bull.

    (1993)
  • J.A. King et al.

    Heterogeneity of vertebrate luteinizing hormone

    Science

    (1979)
  • J.A. King et al.

    Co-ordinated evolution of GnRHs and their receptors

  • N.M. Sherwood

    Origin of mammalian gonadotropin-releasing hormones

    Endocr. Rev.

    (1993)
  • S.C. Sealfon

    Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor

    Endocr. Rev.

    (1997)
  • R.P. Millar

    Gonadotropin releasing hormones and their receptors

  • R.B. White

    Second gene for gonadotropin-releasing hormone in humans

    Proc. Natl Acad. Sci. USA

    (1998)
  • L. Wang

    Three distinct types of gonadotropin-releasing hormone receptor characterized in the bullfrog

    Proc. Natl Acad. Sci USA

    (2001)
  • R. Millar

    A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

    J. Endocrinol.

    (1999)
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