Pawson Adam J, Morgan Kevin, Maudsley Stuart R, Millar Robert P
Human Reproductive Sciences Unit, Medical Research Council, Edinburgh EH16 4SB, UK.
Reproduction. 2003 Sep;126(3):271-8. doi: 10.1530/rep.0.1260271.
Humans may be particularly unusual with respect to the gonadotrophin-releasing hormone (GnRH) control of their reproductive axis in that they possess two distinct GnRH precursor genes, on chromosomes 8p11-p21 and 20p13, but only one conventional GnRH receptor subtype (type I GnRH receptor) encoded within the genome, on chromosome 4. A disrupted human type II GnRH receptor gene homologue is present on chromosome 1q12. The genes encoding GnRH ligand precursors and GnRH receptors have now been characterized in a broad range of vertebrate species, including fish, amphibians and mammals. Ligand precursors and receptors can be categorized into three phylogenetic families. Members of each family exist in primitive vertebrates, whereas mammals exhibit selective loss of ligand precursor and receptor genes. One interpretation of these findings is that each ligand-cognate receptor family may have evolved to fulfil a separate function in reproductive physiology and that species-specific gene inactivation, modification or loss may have occurred during evolution when particular roles have become obsolete or subject to regulation by a different biochemical pathway. Evidence in support of this concept is available following the characterization of the chromosomal loci encoding the human type II GnRH receptor homologue, a rat type II GnRH receptor gene remnant (on rat chromosome 18) and a mouse type II GnRH ligand precursor gene remnant (on mouse chromosome 2). Whether type I GnRH and type II GnRH peptides elicit different signalling responses in humans by activation of the type I GnRH receptor in a cell type-specific fashion remains to be shown. Recent structure-function studies of GnRH ligands and GnRH receptors and their expression patterns in different tissues add further intrigue to this hypothesis by indicating novel roles for GnRH such as neuromodulation of reproductive function and direct regulation of peripheral reproductive tissues. Surprises concerning the complexities of GnRH ligand and receptor function in reproductive endocrinology should continue to emerge in the future.
人类在促性腺激素释放激素（GnRH）对其生殖轴的控制方面可能特别不同寻常，因为他们在8号染色体p11 - p21和20号染色体p13上拥有两个不同的GnRH前体基因，但在基因组中仅编码一种传统的GnRH受体亚型（I型GnRH受体），位于4号染色体上。在1号染色体q12上存在一个破坏的人类II型GnRH受体基因同源物。编码GnRH配体前体和GnRH受体的基因现已在广泛的脊椎动物物种中得到表征，包括鱼类、两栖动物和哺乳动物。配体前体和受体可分为三个系统发育家族。每个家族的成员存在于原始脊椎动物中，而哺乳动物表现出配体前体和受体基因的选择性丢失。对这些发现的一种解释是，每个配体 - 同源受体家族可能已经进化以在生殖生理学中发挥单独的功能，并且在进化过程中，当特定作用变得过时或受到不同生化途径的调节时，可能发生了物种特异性的基因失活、修饰或丢失。在对编码人类II型GnRH受体同源物、大鼠II型GnRH受体基因残余物（位于大鼠18号染色体上）和小鼠II型GnRH配体前体基因残余物（位于小鼠2号染色体上）的染色体位点进行表征之后，有支持这一概念的证据。I型GnRH和II型GnRH肽是否通过以细胞类型特异性方式激活I型GnRH受体在人类中引发不同的信号反应仍有待证明。最近对GnRH配体和GnRH受体的结构 - 功能研究以及它们在不同组织中的表达模式表明GnRH有新的作用，如对生殖功能的神经调节和对外周生殖组织的直接调节，这进一步增加了这一假设的趣味性。关于GnRH配体和受体在生殖内分泌学中功能复杂性的惊喜在未来应该会继续出现。
