Mead E J, Maguire J J, Kuc R E, Davenport A P
Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK.
Br J Pharmacol. 2007 Aug;151(8):1143-53. doi: 10.1038/sj.bjp.0707295. Epub 2007 May 21.
Orphan G-protein-coupled receptors that have recently been paired with their cognate ligand are an often untapped resource for novel drug development. The KISS1 receptor (previously designated GPR54) has been paired with biologically active cleavage peptides of the KiSS-1 gene product, the kisspeptins (KP). The focus of this review is the emerging pharmacology and physiology of the KP. Genetic linkage analysis in humans revealed that mutations in KISS1 (GPR54, AXOR12 or hOT7T175) result in idiopathic hypogonadotrophic hypogonadism and knockout mouse studies confirmed this finding. Identification of KISS1 (GPR54) as a molecular switch for puberty subsequently led to the discovery that KP activate the GnRH cascade. Prior to the role of KISS1 (GPR54) in puberty being described, KP had been shown to be inhibitors of tumour metastasis across a range of cancers. Subsequently the mechanism of this inhibition has been suggested to be via altered cell motility and adhesiveness. PCR detected highest expression of KP and KISS1 (GPR54) in placenta, and changes in KP levels throughout pregnancy and expression in trophoblasts suggests a role in placentation. Placentation and metastasis are invasive processes that require angiogenesis. Investigation of KISS1 (GPR54) and KP in vasculature revealed discrete localisation of KISS1 (GPR54) to blood vessels prone to atherosclerosis and a potent vasoconstrictor action. A role for KP has also been shown in whole body homeostasis. KP are multifunctional peptides and further investigation is required to fully elucidate the complex pathways regulated by these peptides and how these pathways integrate in the whole body system.
最近已与其同源配体配对的孤儿G蛋白偶联受体是新药开发中经常未被利用的资源。KISS1受体（以前称为GPR54）已与KiSS-1基因产物（即亲吻素，KP）的生物活性裂解肽配对。本综述的重点是KP新出现的药理学和生理学。人类的遗传连锁分析表明，KISS1（GPR54、AXOR12或hOT7T175）中的突变会导致特发性低促性腺激素性性腺功能减退，基因敲除小鼠研究证实了这一发现。将KISS1（GPR54）鉴定为青春期的分子开关，随后导致发现KP激活GnRH级联反应。在描述KISS1（GPR54）在青春期中的作用之前，KP已被证明是一系列癌症中肿瘤转移的抑制剂。随后有人提出这种抑制机制是通过改变细胞运动性和黏附性。PCR检测到胎盘组织中KP和KISS1（GPR54）的表达最高，整个孕期KP水平的变化以及滋养层中的表达表明其在胎盘形成中发挥作用。胎盘形成和转移是需要血管生成的侵袭性过程。对脉管系统中的KISS1（GPR54）和KP的研究揭示了KISS1（GPR54）在易患动脉粥样硬化的血管中的离散定位以及强大的血管收缩作用。KP在全身稳态中也发挥作用。KP是多功能肽，需要进一步研究以充分阐明这些肽调节的复杂途径以及这些途径如何在全身系统中整合。
