Enhancement of chloride transport via Ca2+ mobilization in airway epithelial cells by DS-1039, a novel selective GPR39 agonist.

Zinc dysregulation has been reported in various diseases, but the detailed mechanism behind zinc's effects on the body remains largely unknown. G protein-coupled receptor 39 (GPR39) agonists have been used to clarify the pathophysiological role of zinc, given that GPR39 is recognized as a zinc receptor. In this study, we introduce DS-1039, a novel selective GPR39 agonist, and demonstrate its chloride-inducing activity in airway epithelium. DS-1039 exhibited high selectivity for GPR39, showing minimal responses to 168 other G protein-coupled receptors (GPCRs) and 87 molecular targets. DS-1039 demonstrated calcium mobilization and chloride induction activities that were dependent on GPR39 and calcium-activated chloride channels (CaCCs) in a human bronchial epithelial (hBE) cell system. Electrophysiological analysis revealed that DS-1039 induced chloride currents in Ussing chambers using 3D-cultured primary hBE cells. Additionally, DS-1039 caused hyperpolarization in mouse nasal potential difference analysis, an effect that was absent in GPR39-knockout mice. These findings offer new insights into the roles of zinc and GPR39 in chloride regulation within the airway epithelium and position DS-1039 as a promising novel pharmacological agent for treating diseases involving abnormalities of chloride ion transport.