title: GPR35 is a target of the loop diuretic drugs bumetanide and furosemide.
abstract: We report that the loop diuretic drugs bumetanide and furosemide used in the treatment of hypertension are GPR35 agonists. We utilized calcium flux, inositol phosphate accumulation, and dynamic redistribution assays to examine the pharmacology of these compounds on the human, mouse and rat GPR35. While potent on human GPR35, neither bumetanide nor furosemide were active against mouse or rat GPR35. Furthermore, the Na(+)-Cl(-) cotransporter inhibi- tors chlorothiazide and hydrochlorothiazide were inactive against GPR35 in all three species. We also demonstrate that GPR35 is expressed in human skin where it has been shown that loop diuretics inhibit histamine-induced flare and itch response. These findings suggest that GPR35 may play an important role in skin cell biology and be a potential target for the treatment of a variety of immune disorders.
authors.affiliation: Department of Metabolic Disorders, Amgen San Francisco, South San Francisco, Calif. 94080, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Yang
authors.forename: Angela
authors.initials: A
authors.lastname: Fu
authors.forename: Xiaosu
authors.initials: X
authors.lastname: Wu
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Reagan
mesh_terms: D000818:Animals; D002034:Bumetanide / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002740:Chlorothiazide / Q000494:pharmacology; D006224:Cricetinae; D004232:Diuretics / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology*; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000096:biosynthesis; D012867:Skin / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D004232:Diuretics; C111379:GPR35 protein, human; C513986:GPR35 protein, mouse; C513985:GPR35 protein, rat; D007295:Inositol Phosphates; D043562:Receptors, G-Protein-Coupled; D006852:Hydrochlorothiazide; D002034:Bumetanide; D002740:Chlorothiazide; D005665:Furosemide; D002118:Calcium