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

Lihua Liang, Kelvin MacDonald, Erik M. Schwiebert, Pamela L. Zeitlin, William B. Guggino

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)C131-C141
JournalAmerican Journal of Physiology - Cell Physiology
Volume296
Issue number1
DOIs
StatePublished - Jan 1 2009

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Keywords

  • Calcium-activated chloride channel
  • Cystic fibrosis therapy

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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