Capra Valérie
Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Pharmacol Res. 2004 Jul;50(1):1-11. doi: 10.1016/j.phrs.2003.12.012.
The cysteinyl leukotrienes (cys-LTs), i.e. LTC(4), LTD(4) and LTE(4), trigger contractile and inflammatory processes through the specific interaction with cell surface receptors belonging to the purine receptor cluster of the rhodopsin family of the G protein-coupled receptor (GPCR) genes. Cys-LTs have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in a number of inflammatory conditions including cardiovascular and gastrointestinal diseases. Pharmacological studies have identified two classes of cys-LT receptors (CysLT(1) and CysLT(2)) based on their sensitivity to CysLT(1) selective antagonists, albeit there is evidence for additional subtypes. Molecular cloning of the human CysLT(1) and CysLT(2) receptors has confirmed both their structure as putative seven transmembrane domain G protein-coupled receptors and most of the previous pharmacological characterization. The rank order of potency of agonist activation for the CysLT(1) receptor is LTD4 > LTC4 > LTE4 and for the CysLT(2) receptor is LTC4 = LTD4 > LTE4. The CysLT(1) receptor is most highly expressed in spleen, peripheral blood leukocytes, interstitial lung macrophages and in airway smooth muscle. The CysLT(2) receptor is mostly expressed in heart, adrenals, placenta, spleen, peripheral blood leukocytes and less strongly in the brain. Gene cloning of CysLT(1) and CysLT(2) receptors has renewed the attention on the cys-LTs field and will, hopefully, encourage future studies on the regulation of CysLT receptors expression and the dissection of their signalling pathways. Furthermore, the peculiar pattern of expression of the two receptor subtypes will promote the discovery of new functions for cys-LTs in physiological and pathological conditions. Only CysLT(1) selective receptor antagonists have been described to date and are currently available for the treatment of asthma. Molecular cloning of different CysLT receptor subtypes will certainly foster the development of new selective antagonists based on molecular modelling studies.
半胱氨酰白三烯（cys-LTs），即LTC(4)、LTD(4)和LTE(4)，通过与属于G蛋白偶联受体（GPCR）基因视紫红质家族嘌呤受体簇的细胞表面受体特异性相互作用，触发收缩和炎症过程。Cys-LTs在诸如哮喘、过敏性鼻炎和其他鼻部过敏等病理生理状况中具有明确作用，并且与包括心血管和胃肠道疾病在内的多种炎症状况有关。药理学研究基于对CysLT(1)选择性拮抗剂的敏感性，确定了两类半胱氨酰白三烯受体（CysLT(1)和CysLT(2)），尽管有证据表明还存在其他亚型。人CysLT(1)和CysLT(2)受体的分子克隆已证实它们作为假定的七跨膜结构域G蛋白偶联受体的结构以及先前的大部分药理学特征。CysLT(1)受体激动剂激活的效力顺序为LTD4 > LTC4 > LTE4，而CysLT(2)受体的为LTC4 = LTD4 > LTE4。CysLT(1)受体在脾脏、外周血白细胞、肺间质巨噬细胞和气道平滑肌中表达最高。CysLT(2)受体主要在心脏、肾上腺、胎盘、脾脏、外周血白细胞中表达，在脑中表达较弱。CysLT(1)和CysLT(2)受体的基因克隆重新引起了对半胱氨酰白三烯领域的关注，并有望鼓励未来对CysLT受体表达调控及其信号通路解析的研究。此外，两种受体亚型独特的表达模式将促进在生理和病理状况下发现半胱氨酰白三烯的新功能。迄今为止，仅描述了CysLT(1)选择性受体拮抗剂，目前可用于治疗哮喘。不同CysLT受体亚型的分子克隆肯定会基于分子建模研究促进新型选择性拮抗剂的开发。
