A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha :

Chronic obstructive pulmonary disease (COPD) and asthma are the major causes of pulmonary disability in the United States, with at least 10 million Americans suffering form COPD and up to 5% of the population afflicted with asthma. Over the past 20 years, major strides have been made in our understanding of the pathophysiology of these disorders, although there are still large gaps in our knowledge. While a number of position papers and statements have been promulgated by the American Thoracic Society concerning various aspects of the diagnosis and treatment of COPD and asthma, it was felt that a review of the overall topic was timely. This statement represents the combined efforts of a Task Group appointed by the Scientific Assemble of Clinical Problems of the American Thoracic Society to accomplish this task. Clearly, we could not cover every aspect of this broad topic nor even provide a detailed review of those areas addressed. We elected instead to concentrate on clinically relevant topics and to provide sufficient data to be useful as a guide as well as to include selected, but in no was exhaustive, references. The first two chapters define the entities and set forth recommendations for diagnosis, hospital admission, and discharge. The remaining four chapters critically review the various facets of therapy. We have noted controversial areas and those were conclusive experimental data are not yet available. In these situations, the committee often decided to take a position on one side or the other based upon the best available information.

The cysteinyl leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.

The contractile and inflammatory actions of the cysteinyl leukotrienes (CysLTs), LTC(4), LTD(4), and LTE(4), are thought to be mediated through at least two distinct but related CysLT G protein-coupled receptors. The human CysLT(1) receptor has been recently cloned and characterized. We describe here the cloning and characterization of the second cysteinyl leukotriene receptor, CysLT(2), a 346-amino acid protein with 38% amino acid identity to the CysLT(1) receptor. The recombinant human CysLT(2) receptor was expressed in Xenopus oocytes and HEK293T cells and shown to couple to elevation of intracellular calcium when activated by LTC(4), LTD(4), or LTE(4). Analyses of radiolabeled LTD(4) binding to the recombinant CysLT(2) receptor demonstrated high affinity binding and a rank order of potency for competition of LTC(4) = LTD(4) LTE(4). In contrast to the dual CysLT(1)/CysLT(2) antagonist, BAY u9773, the CysLT(1) receptor-selective antagonists MK-571, montelukast (Singulair(TM)), zafirlukast (Accolate(TM)), and pranlukast (Onon(TM)) exhibited low potency in competition for LTD(4) binding and as antagonists of CysLT(2) receptor signaling. CysLT(2) receptor mRNA was detected in lung macrophages and airway smooth muscle, cardiac Purkinje cells, adrenal medulla cells, peripheral blood leukocytes, and brain, and the receptor gene was mapped to chromosome 13q14, a region linked to atopic asthma.