Guinea pig cysteinyl leukotriene receptor 2 (gpCysLT2) mediates cell proliferation and intracellular calcium mobilization by LTC4 and LTD4

Abstract

We cloned and pharmacologically characterized the guinea pig cysteinyl leukotriene (CysLT) 2 receptor (gpCysLT2). gpCysLT2 consists of 317 amino acids with 75.3%, 75.2%, 73.3% identity to those of humans, mice and rats, respectively. The gpCysLT2 gene is highly expressed in the lung, moderately in eosinophils, skin, spleen, stomach, colon, and modestly in the small intestine. CysLTs accelerated the proliferation of gpCysLT2-expressing HEK293. Leukotriene C4 (LTC4) and Leukotriene D4 (LTD4) enhanced the cell proliferation higher than Bay-u9773, a CysLT2 selective partial agonist and a nonselective antagonist for CysLT receptors. Bay-u9773 did not antagonize the cell proliferation by LTC4 and LTD4. Despite the equipotency of the mitogenic effect among these chemicals, calcium mobilization (CM) levels were variable (LTC4＞ LTD4＞＞ Bay-u9773), and Bay-u9773 antagonized the CM by LTC4. Moreover, the Gi/o inhibitor pertussis toxin perfectly inhibited agonist-induced cell proliferation. These results reveal that cell proliferation via CysLT2 signaling was mediated by Gi/o signaling but independent of calcium mobilization. [BMB reports 2008; 41(2): 139-145]

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma

“…LTC 4 is reported to be a guinea pig CysLT 2 selective ligand, unlike the case in humans. , It is difficult to evaluate pharmacological effects involving CysLT 2 in guinea pigs because LTC 4 is immediately metabolized by γ-glutamyltranspeptidase. Yonetomi et al reported a novel asthmatic model mediated via the CysLT 2 receptor in guinea pigs .…”

Effects of a Cysteinyl Leukotriene Dual 1/2 Receptor Antagonist on Antigen-Induced Airway Hypersensitivity and Airway Inflammation in a Guinea Pig Asthma Model

“…Expression of the cysLT2 receptor prevailed over that of the cysLT1 receptor in human bronchial epithelial cells (line BEAS-2B) [25]. There is increasing evidence of an important role for cysLT2 in chronic inflammation [16]. Furthermore, genetic analysis revealed that the human cysLT2 locus (13q14) is associated with atopic asthma [3].…”

“…The guinea pig cysLT2 receptor gene is expressed highly in the lung and moderately in eosinophils [16]. Significant upregulation of cysLT1 receptor and cysLT2 receptor mRNA expression was induced by antigen challenge in the lungs of BALB/c mice [24].…”

“…CysLTs mediate their effects by binding to specific cell surface receptors designated cysLT1 and cysLT2 [16]. CysLT1 and cysLT2 have been shown to exert distinct functions [17].…”

Immunopharmacological role of the Leukotriene Receptor Antagonists and inhibitors of leukotrienes generating enzymes in Multiple Sclerosis

“…Binding of cysLTs to their receptors could leadto broncho-constriction and asthma, chemotaxis, and proliferation and survival of some cells such as, smooth muscle cells [154], mucus exudation, neuronal lesion [155], vascular permeability [156], hyperplasia of smooth muscle cells, subepithelial fibrosis [157], P-selectin expression and secretion of platelets aggregator factors such as von Willebrand [158].…”