title: G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium.
abstract: We report that the asthma drugs cromolyn disodium and nedocromil sodium are potent G-protein-coupled receptor 35 (GPR35) agonists. We utilized calcium flux and inositol phosphate accumulation assays to examine the pharmacology of these asthma drugs on the human, mouse and rat GPR35. The compounds were more potent on the human GPR35 than on mouse and rat receptors. In contrast, zaprinast, a known GPR35 agonist, was more potent on mouse and rat GPR35 than the human ortholog. We show by quantitative PCR that GPR35 is expressed in human mast cells, human basophils and human eosinophils. We also demonstrate that GPR35 mRNA is upregulated upon challenge with IgE antibodies. We show that, unlike zaprinast, a potent phosphodiesterase 5 (PDE5) inhibitor, cromolyn disodium and nedocromil sodium lack inhibitory activity towards PDE5. These findings suggest that GPR35 may play an important role in mast cell biology and be a potential target for the treatment of asthma.
authors.affiliation: Department of Metabolic Disorders, Amgen San Francisco, South San Francisco, CA 94080, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Yang
authors.forename: Jenny Ying-Lin
authors.initials: JY
authors.lastname: Lu
authors.forename: Xiaosu
authors.initials: X
authors.lastname: Wu
authors.forename: Shamin
authors.initials: S
authors.lastname: Summer
authors.forename: John
authors.initials: J
authors.lastname: Whoriskey
authors.forename: Christiaan
authors.initials: C
authors.lastname: Saris
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Reagan
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001491:Basophils / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004205:Cromolyn Sodium / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000494:pharmacology; D066298:In Vitro Techniques; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017835:Nedocromil / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000096:biosynthesis
chemical_list: D018927:Anti-Asthmatic Agents; C111379:GPR35 protein, human; C513986:GPR35 protein, mouse; C513985:GPR35 protein, rat; D058986:Phosphodiesterase 5 Inhibitors; D011688:Purinones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D017835:Nedocromil; D007073:Immunoglobulin E; C011145:zaprinast; D004205:Cromolyn Sodium