Kiss1/Kiss1受体系统与生殖功能的研究进展
2017年11月
中华口腔医学杂志，第33卷第11期 第1001页-第1006页
蔡梁椿,温俊平,陈刚
参考文献
由施维雅(达美康缓释片)特别赞助]参考文献
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1996年，Lee等[1]发现了一种抑制恶性黑色素瘤转移的基因，因为发现的地点位于宾夕法尼亚州著名的"kisses"巧克力的家乡赫尔希小城，该基因被命名为Kiss1，而"SS"更代表了"suppressor sequence(抑制序列)"，暗示其抑制肿瘤转移的作用。在人类中，Kiss1基因位于染色体1q32，其编码不稳定且无生物活性的含145个氨基酸的前肽，然后被转换成4种有生物活性的肽，统称为Kisspeptins。Kisspeptin在胎盘、下丘脑、垂体和性腺中都有表达[2,3]。人类Kisspeptins基于其氨基酸的数量被区分并命名为：Kisspeptin-54、14、13和10[2,4,5,6]；而在在啮齿类动物，Kisspeptin-52被认为是片段最长的内源活性Kisspeptin[7]。Kisspeptins属于RF-酰胺肽超家族，此家族成员的特征在于其C-末端含有Arg-Phe-NH2序列[8]。Kisspeptins是GPR(G蛋白偶联受体)的天然配体，几个独立的研究团队发现了该受体并研究了其生理功能，该受体的曾用名包括GPR54，AXOR12，hOT7T175，Kiss1R/Kiss1r，CPPB1，HH8和KiSS-1R[2,5,6,9,10]。而在这些不同的名称中，Kiss1R/Kiss1r的使用已经成为了共识[8,10]。人类Kiss1R基因位于染色体19p13.3，其编码的蛋白是一个拥有398个氨基酸的肽，而大鼠Kiss1r编码的蛋白则含有396个氨基酸[6,9]。Kiss1R是7次跨膜受体，其跨膜部分与甘丙肽受体具有高度同源性，但是甘丙肽不会结合或激活Kiss1R[9,11]。
Kiss1R是GPRs大家族的成员之一，其属于Gq/11蛋白相关受体的亚组。Kisspeptin结合磷脂双分子层上的Kiss1r后，磷酸化的Gq/11蛋白激活PLC-β(phospholipase C-β，磷脂酶C-β)。激活的PLC-β通过水解作用使细胞膜上的磷脂PIP2(phosphatidylinositol-4，5-bisphosphate，二磷酸磷脂酰肌醇)转化以形成IP3(inositol 1，4，5-triphosphate，肌醇1，4，5-三磷酸)和DAG(diacylglycerol，甘油二酯)。DAG激活PKC(protein kinase C，蛋白激酶C)，并且IP3结合并激活内质网的膜上的Ca2＋通道，引起Ca2＋释放至细胞浆[5,6]。除了Gq-PLC-Ca2＋通路，Kisspeptin还能诱导其他细胞内信号转导通路，包括MAPK(mitogen-activated protein kinases，丝裂原活化蛋白激酶)/ERK(extracellular signal-regulated kinase pathway，细胞外信号调节激酶)通路和Rho激酶通路[5,6,12,13,14]。
HPG轴(hypothalamic-pituitary-gonadal axis，下丘脑-垂体-性腺轴)是维持青春期发育与生殖功能的关键。GnRH(Gonadotropin-Releasing Hormone，促性腺激素释放激素)刺激垂体LH(Luteinizing Hormone，促黄体生成素)分泌，LH的脉冲释放峰值及其脉冲频率的增加会导致睾丸或卵巢产生睾酮或雌二醇，促进青春期发育与成熟，对生殖有重要的作用。Kiss1/Kiss1R系统是GnRH的最有效的促泌剂[15]，是GnRH脉冲发生的上游分子，参与了青春期启动及与生殖轴相关的能量代谢[8,16,17,18,19,20,21]。
在人类，GnRH神经元定位在下丘脑视前区到漏斗核(infundibular nucleus)，而啮齿动物中，GnRH神经元主要存在于视前区[22,23]。GnRH轴突从这些核团伸出轴突投射到正中隆起，以脉冲的方式将GnRH释放到门脉循环。与GnRH神经元类似地，在包括人类的所有物种中，下丘脑漏斗核以及弓状核都有Kisspeptin神经元。但是该神经元在下丘脑头端区(rostralpreoptic area)的分布存在物种特异性：在该区域，人类的Kisspeptin神经元主要分散于视前区中，而啮齿动物的Kisspeptin神经元在该区域主要定位于第三脑室室周的AVPV(anteroventral periventricular nucleus)核和PeN核(periventricular nucleus)中[24,25,26,27,28]。在人类，Kisspeptin神经元的轴突在漏斗柄(infundibular stalk)中形成致密的毛细血管丛，而此处正是GnRH神经分泌的位置[28]。在啮齿类动物、绵羊和猴子中也发现，漏斗柄处可见Kisspeptin和GnRH神经元之间的轴突-细胞体，轴突-树突和轴突-轴突的接触，Kisspeptin和GnRH神经元网络密切联系[15,16,24,26,28,29,30,31]。这些解剖学上的发现表明Kisspeptin可能直接参与GnRH的神经分泌。另外，在啮齿动物、绵羊等一系列哺乳动物ARC(Arcuate nucleus，弓状核)中发现了一神经元群，在这一神经元群中，Kisspeptin与neurokinin B(神经激肽B)和dynorphin(强啡肽)共定位，该神经元群统称为KNDy神经元(Kisspeptin /neurokinin B /dynorphin Neurons)。在KNDy神经元网络中，neurokinin B发挥促进作用，而dynorphin引起抑制，它们共同作用，调节Kisspeptin的脉冲释放[32]，继而调节GnRH神经元。
与上述解剖学的研究结果相呼应的是，动物研究表明Kisspeptin可直接作用于下丘脑GnRH神经元，刺激GnRH分泌。Kisspeptin导致体外GnRH神经元的去极化和放电速率(firing rate)的增加[16,33]；Kisspeptin能刺激下丘脑外植体中GnRH的分泌[34,35]。Kisspeptin暴露后，GnRH神经元的细胞体内GnRH mRNA的表达上调[36]。在绵羊脑室内输注Kisspeptin会引起脑脊液GnRH含量的急剧增加，血清LH和FSH (follicle-stimulating hormone，卵泡刺激素)也同时增加[31]。Kisspeptin诱导的GnRH神经元放电会被Kisspeptin拮抗剂所消除[37]。将Kisspeptin的拮抗剂注射到青春期恒河猴的正中隆起会导致GnRH脉冲释放减少，证明Kisspeptin是GnRH的脉冲释放所必需的[37]。大鼠的弓状核是GnRH脉冲发生器的位置，将Kisspeptin拮抗剂注射到弓状核会导致LH脉冲频率减少，而注射到视前区则不会出现该现象，说明Kisspeptin在大鼠的弓状核调节GnRH的分泌[38]。GnRH拮抗剂的预处理会抑制Kisspeptin对LH释放的作用，进一步证明Kisspeptin通过GnRH来调控LH的释放，Kisspeptin处于GnRH的上游[19]。Kiss1/Kiss1R基因失活突变会变现出IHH(idiopathic hypogonadotropichypogonadism，特发性低促性腺激素性性腺功能减退症，这种疾病是由于垂体促性腺激素FSH和LH分泌不足引起的性腺功能障碍)[39,40]。而在IHH患者中也发现了Kiss1/Kiss1R基因的纯合或杂合失活突变[41,42]。而Kiss1R激活突变会引起性早熟[43,44]。这些都表明Kisspeptin调节GnRH脉冲释放。
虽然研究已表明Kisspeptin直接作用于GnRH神经元以触发GnRH分泌，GnRH直接作用于垂体以触发gonadotropin(促性腺激素)释放，然而研究也证明各物种的垂体表达Kiss1和Kiss1r[45,46]，Kisspeptin可直接作用于大鼠、小鼠、猪和牛分离的垂体细胞，调节促性腺激素的基因表达和分泌[47,48,49]。Witham等[49]还报道，Kisspeptin可增强小鼠垂体LβT2细胞Egr-1(early growth response factor-1，早期生长反应因子1)和cFos启动子的转录活性；且当雌二醇诱导出现LH脉冲峰值时，雌性小鼠的垂体Kiss1r表达增加。这些结果提示Kisspeptin信号能调节垂体的基因表达，进而调控生殖功能。尽管有了上述的发现，然后有一系列研究也证明了GnRH拮抗剂可以阻断Kisspeptin诱导的促性腺激素分泌的增加，如在成年小鼠和大鼠中，注射GnRH拮抗剂会抑制Kisspeptin对LH释放的作用[15,18,45,50,51]，表明Kisspeptin依赖性促性腺激素的大量分泌应该是由于GnRH的直接激活导致的。Navarro等[51]的研究发现在大鼠垂体外植物中，Kisspeptin无法直接调节基础FSH分泌，但能显著地增强GnRH刺激的FSH分泌。因此，作者认为Kisspeptin在垂体对FSH释放的直接贡献很小。
Kiss1/Kiss1R信号在卵巢生理学中具有重要作用。在大鼠的卵巢和子宫中，检测到Kiss1/Kiss1R基因mRNA的表达[7]。免疫组织化学分析随后证实了Kisspeptin和/或其受体在大鼠的卵巢和输卵管[52,53,54]以及人的卵巢、输卵管和子宫中表达[54,55]。这些研究提示Kiss1/Kiss1R系统对妊娠的调节可能是独立于神经内分泌轴而直接在卵巢和子宫水平。据报道Kiss1r功能障碍会导致卵巢功能早衰，这是育龄期女性不育的主要原因之一[56,57]。在大鼠中，Kiss1 mRNA的水平会随着发情周期而改变，在排卵前显著地增加[52]。Castellano等[52]进一步证明，阻断排卵前促性腺激素激增可以抑制Kiss1在排卵前的升高。Shahed等[58]报道，在光抑制的西伯利亚仓鼠中，卵巢Kisspeptin和Kiss1r水平降低。鉴于这些发现，研究者认为源于卵巢的Kisspeptin对排卵时或者排卵后的卵巢激素的生成可能起了直接的调控作用。
已证明Kisspeptin在小鼠的睾丸Leydig细胞表达和分泌。在人类的精子的头部，颈部和鞭毛中也可检测到Kisspeptin和Kiss1R的表达。Kisspeptin干预可以触发人类和小鼠精子细胞内Ca2＋逐渐增加。Kisspeptin还能诱导精子瞬时激活，调节精子的运动，Kiss1R拮抗剂可阻断此过程。基于这些结果，Pinto等[59]认为Kisspeptin可能直接在男性精子水平调节男性生育能力。在小鼠中的Leydig细胞、曲精小管和精子细胞中也检测到Kiss1和Kiss1r，Kiss1R在精子细胞的顶体区域和成熟精子中也有表达[60,61]达。然而，Mei等[60]在永生化Leydig细胞系MA-10中发现Kisspeptin不能触发孕酮释放。他们还测试了Kisspeptin是否可以直接刺激睾丸释放睾酮，同样没有发现任何响应。因此他们认为在小鼠睾丸中Kisspeptin没有明显的作用。但是在人的精子中，Kisspeptin似乎可以调节精子的功能，因为Hsu等[61]发现，用Kiss1R拮抗剂处理精子后，体外受精率降低了，Kisspeptin似乎可以调节哺乳动物的受精过程。
Kiss1/Kiss1R信号对青春期具有重要作用。在2003年，两个独立的研究组De Roux等和Seminara等证明，在低促性腺激素性性腺机能减退症的患者中，Kiss1R中的失活点突变和缺失与青春期发育障碍相关[39,40]。Kiss1R的突变在血亲家庭和无血缘关系的患者中同时发现。此外，Kiss1r和Kiss1基因缺失的小鼠拥有几乎相同的表型[40,62,63]。在性早熟的女孩患者中也发现了Kiss1R基因的激活突变，人类Kiss1R基因激活突变会导致性腺过早地从青春期前的无活性状态向青春期后的激活的生殖状态转变[43,44]。在三个不相关的中枢性早熟儿童患者中发现了Kiss1基因的错义突变[64]，这种突变的基因编码的Kisspeptin对体外降解具有更强的抵抗性，提示其引起性早熟可能是因为拥有更大的生物活性及利用度[64]。在啮齿动物和灵长类动物的下丘脑中，Kiss1和Kiss1r基因的mRNA在青春期时表达显著上调[16,18,65]。幼年和成年小鼠大部分的GnRH神经元中表达Kiss1R mRNA，且Kisspeptin能够调控GnRH，在青春期启动中扮演了重要角色[16]。能对Kisspeptin干预产生去极化的GnRH神经元的百分比从幼年、青春期到成年逐渐上升，说明GnRH神经元在青春期的过程中，获得了对Kisspeptin的敏感性[18]。青春期开始时，猴Kisspeptin-54分泌，特别是其分泌的脉冲频率明显增加[66]。除了这些生理变化可让我们将Kisspeptin信号传导与青春期的发生联系起来以外，给予外源Kisspeptin也会导致大鼠和猴的青春期提前[67,68]。相反，Kisspeptin拮抗剂则抑制了猴青春期时的GnRH脉冲释放，导致了大鼠的青春期延迟[37,69]。这些发现强烈支持了在一系列物种中，Kiss1/Kiss1R信号在青春期启动和进展中是必不可少的。
在下丘脑，性腺类固醇激素可以通过反馈作用调节Kiss1基因mRNA表达[70]。在下丘脑GT1-7细胞中，雌激素可以上调Kiss1基因的表达[71]。动物实验中，E2可抑制下丘脑ARC中Kisspeptin表达，刺激AVPV中的Kisspeptin表达[72,73,74]。此外，代谢状态也能调节Kiss1基因的表达。代谢应激如长期高脂饮食或禁食会导致Kiss1基因表达下降[75,76]。在生理上，对由于低能量而导致获得性GnRH缺乏的妇女注射Kisspeptin可以刺激GnRH/LH释放[77,78]，表明神经内分泌营养信号的整合要么位于Kisspeptin神经元的上游，要么就在Kisspeptin神经元处。与能量代谢相关的激素如leptin、insulin和ghrelin被认为是介导生殖代谢调控的关键分子。目前尚不清楚这些激素是通过哪些神经回路来发挥它们对GnRH的调控作用。有研究显示部分的ARC的Kisspeptin神经元表达LepR(leptin receptor)基因[79]，但并未发现直接的leptin-Kisspeptin信号[75]。一些Kisspeptin免疫阳性神经元中也发现了InsR(insulin receptors)蛋白表达[80]。而用leptin干预ob/ob小鼠，能够增加Kiss1基因mRNA表达[79]，而用ghrelin干预自由进食的大鼠则导致Kisspeptin的表达下调以及LH脉冲的频率减少[81]。此外，insulin依赖性糖尿病大鼠显示出Kisspeptin mRNA表达的减少，有趣的是，insulin的干预没有使减少的Kisspeptin基因回复表达，而leptin的干预却能够使Kiss1 mRNA的表达和LH浓度回到正常水平[82]。虽然充分的证据表明Leptin和insulin可以调节Kisspeptin神经元，但是正常生殖功能似乎并不需要它们的直接作用，如特异性Kisspeptin神经元InsR或LepR缺失的小鼠仍能够保持正常的HPG轴的功能[80,83]。这些小鼠完全可育，但会出现青春期的延时[84]。ARC中存在POMC[pro-opiomelanocortin，阿片促黑皮质素原，是一种能够抑制食欲的melanocortin(黑皮质素)肽的前体]和NPY(neuropeptide Y，神经肽Y)神经元，它们在能量代谢中起着相反的作用。POMC神经元能够促进饱食感、抑制进食[85,86]，而NPY神经元则能促进食欲[87]。最近Manfredi-Lozano等[88]报道了一种新型的leptin-melanocortin-Kisspeptin-GnRH信号通路。Leptin对Kisspeptin的作用有可能是由POMC神经元介导的。相反，另外的研究表明，Kisspeptin能直接兴奋POMC神经元，间接抑制NPY神经元的活动[89]。因此，Kisspeptin在将营养状态传递给GnRH神经元的过程中，似乎既是POMC神经元的上游分子，又处于POMC神经元的下游。有趣的是，2015年有一项研究显示ARC中超过一半的Kisspeptin神经元源自于表达POMC的祖细胞[90]。产前营养不良会损害下丘脑melanocortin系统的发育并引起能量代谢失衡[91]，因此上述研究可能可以部分解释为什么产前营养不良会引起生殖损害[92]。
2005年Dhillo等[93]首次用KP-54(Kisspeptin-54)对健康男性进行90 min的静脉注射，发现LH显著增加，且其浓度接近了最高水平，FSH和血清睾酮也显著增加。另一项研究比较了在健康男性中KP-10和KP-54注射的作用，发现二者对LH和FSH的增加程度相似[94]；在健康女性中，皮下注射KP-54引起了LH脉冲数量增加及其间隔时间缩短[95]。能量平衡在生殖中处于核心地位，营养不良和过度营养均会影响生殖过程。在能量代谢方面，Kisspeptin可用于治疗多种继发于代谢紊乱的性腺功能减退症。对雄性恒河猴进行禁食，其Kiss1基因的mRNA的表达会被抑制，对青春期大鼠采取同样的干预措施，也会出现类似的情况，而Kisspeptin的注射能够恢复其促性腺激素的水平和青春期过程[76,96]。2型糖尿病和肥胖症会导致循环中促性腺激素水平降低，原因可能是因为GnRH分泌减少[97]。对糖尿病大鼠、糖尿病合并肥胖症患者的研究发现Kisspeptin表达下降，外源注射Kisspeptin可以增加LH的脉冲分泌，睾酮水平也增加[82]。Kisspeptin还可应用于体外受精的妇女，刺激LH释放峰值，诱发排卵，且其可能具有hCG(Human chorionic gonadotropin，人绒毛膜促性腺激素)没有的优势[98,99]。