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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Spiperone, identified through compound screening, activates calcium-dependent chloride secretion in the airway

Departments of ¹Physiology and ²Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; and ³Discovery Biomed LLC, Birmingham, Alabama

Submitted 2 July 2008 ; accepted in final form 4 November 2008

Cystic fibrosis (CF) is caused by mutations in the gene producing the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a Cl^– channel. Its dysfunction limits Cl^– secretion and enhances Na⁺ absorption, leading to viscous mucus in the airway. Ca²⁺-activated Cl^– channels (CaCCs) are coexpressed with CFTR in the airway surface epithelia. Increases in cytosolic Ca²⁺ activate the epithelial CaCCs, which provides an alternative Cl^– secretory pathway in CF. We developed a screening assay and screened a library for compounds that could enhance cytoplasmic Ca²⁺, activate the CaCC, and increase Cl^– secretion. We found that spiperone, a known antipsychotic drug, is a potent intracellular Ca²⁺ enhancer and demonstrated that it stimulates intracellular Ca²⁺, not by acting in its well-known role as an antagonist of serotonin 5-HT₂ or dopamine D₂ receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Spiperone activates CaCCs, which stimulates Cl^– secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro and in CFTR-knockout mice in vivo. In conclusion, we have identified spiperone as a new therapeutic platform for correction of defective Cl^– secretion in CF via a pathway independent of CFTR.

cystic fibrosis therapy; calcium-activated chloride channel