Millar Robert P, Babwah Andy V
Mammal Research Institute, University of Pretoria, Pretoria, South Africa.
Neuroendocrinology. 2015;101(3):193-210. doi: 10.1159/000381457. Epub 2015 Mar 13.
Kisspeptin (KP) is now well recognized as a potent stimulator of gonadotropin-releasing hormone (GnRH) secretion and thereby a major regulator of the neuroendocrine-reproductive axis. KP signals via KISS1R, a G protein-coupled receptor (GPCR) that activates the G proteins Gαq/11. Modulation of the interaction of KP with KISS1R is therefore a potential new therapeutic target for stimulating (in infertility) or inhibiting (in hormone-dependent diseases) the reproductive hormone cascade. Major efforts are underway to target KISS1R in the treatment of sex steroid hormone-dependent disorders and to stimulate endogenous hormonal responses along the neuroendocrine axis as part of in vitro fertilization protocols. The development of analogs modulating KISS1R signaling will be aided by an understanding of the intracellular pathways and dynamics of KISS1R signaling under normal and pathological conditions. This review focuses on KISS1R recruitment of intracellular signaling (Gαq/11- and β-arrestin-dependent) pathways that mediate GnRH secretion and the respective roles of rapid desensitization, internalization, and recycling of resensitized receptors in maintaining an active population of KISS1R at the cell surface to facilitate prolonged KP signaling. Additionally, this review summarizes and discusses the major findings of an array of studies examining the desensitization of KP signaling in man, domestic and laboratory animals. This discussion highlights the major effects of ligand efficacy and concentration and the physiological, developmental, and metabolic status of the organism on KP signaling. Finally, the potential for the utilization of KP and analogs in stimulating and inhibiting the reproductive hormone cascade as an alternative to targeting the downstream GnRH receptor is discussed.
如今，亲吻素（KP）已被公认为促性腺激素释放激素（GnRH）分泌的强效刺激物，因此是神经内分泌-生殖轴的主要调节因子。KP 通过 KISS1R 信号传导，KISS1R 是一种 G 蛋白偶联受体（GPCR），可激活 G 蛋白 Gαq/11。因此，调节 KP 与 KISS1R 的相互作用是刺激（用于治疗不孕症）或抑制（用于治疗激素依赖性疾病）生殖激素级联反应的潜在新治疗靶点。目前正在大力开展针对 KISS1R 治疗性类固醇激素依赖性疾病以及刺激神经内分泌轴内源性激素反应的研究，这也是体外受精方案的一部分。了解正常和病理条件下 KISS1R 信号传导的细胞内途径和动态变化，将有助于开发调节 KISS1R 信号传导的类似物。本综述重点关注 KISS1R 募集介导 GnRH 分泌的细胞内信号传导途径（依赖 Gαq/11 和 β-抑制蛋白），以及快速脱敏、内化和再敏化受体的再循环在维持细胞表面活性 KISS1R 群体以促进 KP 信号长期传导方面的各自作用。此外，本综述总结并讨论了一系列研究人类、家畜和实验动物中 KP 信号脱敏的主要发现。该讨论突出了配体效力和浓度以及生物体的生理、发育和代谢状态对 KP 信号传导的主要影响。最后，讨论了利用 KP 及其类似物刺激和抑制生殖激素级联反应作为靶向下游 GnRH 受体替代方法的潜力。
