Thompson Miles D, Xhaard Henri, Sakurai Takeshi, Rainero Innocenzo, Kukkonen Jyrki P
University of Toronto Epilepsy Research Program, Department of Pharmacology, University of Toronto Toronto, ON, Canada.
Faculty of Pharmacy, Centre for Drug Research, University of Helsinki Helsinki, Finland.
Front Neurosci. 2014 May 6;8:57. doi: 10.3389/fnins.2014.00057. eCollection 2014.
Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts the involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are discussed. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated-with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency-leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics) is also discussed in the review.
食欲素/下丘脑分泌素肽突变在人类中较为罕见。尽管人类发作性睡病与食欲素缺乏有关，但这极少是由于编码前食欲素原（两种食欲素肽的前体）的基因突变所致。相比之下，在许多人群中已鉴定出OX1和OX2食欲素受体的编码和非编码变体；有时，这些变体与疾病表型相关，尽管大多数仅带来相对较低的风险。在大多数情况下，这些研究基于候选基因假说，该假说预测食欲素参与相关的病理生理过程。在本综述中，将讨论已知的人类OX1/HCRTR1和OX2/HCRTR2基因变体/多态性，以及关于它们参与发作性睡病、日间过度嗜睡、丛集性头痛、精神分裂症中的烦渴低钠血症和情感障碍等疾病的研究。在大多数情况下，食欲素变体的功能细胞或药理学相关性尚未得到研究——OX2的氨基酸10 Pro/Ser变体对食欲素效力可能产生的影响除外——这使得关于受体变体效应性质的结论具有推测性。尽管如此，我们提出了可为进一步研究奠定基础的观点。食欲素受体变体的药理学及其他特性将在GPCR信号传导的背景下进行讨论。由于食欲素能疗法正在兴起，受体变体对配体亲和力或效力的影响值得考虑。本综述中也讨论了这一观点（药物遗传学）。
