RNA interference targeted to multiple P2X receptor subtypes attenuates zinc-induced calcium entry

Lihua Liang, Akos Zsembery, Erik M. Schwiebert

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

A postulated therapeutic avenue in cystic fibrosis (CF) is activation of Ca2+-dependent Cl- channels via stimulation of Ca 2+ entry from extracellular solutions independent of CFTR functional status. We have shown that extracellular zinc and ATP induce a sustained increase in cytosolic Ca2+ in human airway epithelial cells that translates into stimulation of sustained secretory Cl- transport in non-CF and CF human and mouse airway epithelial cells, cell monolayers, and nasal mucosa. On the basis of these studies, the Ca2+ entry channels most likely involved were P2X purinergic receptor channels. In the present study, molecular and biochemical data show coexpression of P2X4, P2X5, and P2X6 subtypes in non-CF (16HBE14 o-) and CF (IB3-1) human bronchial epithelial cells. Other P2X receptor Ca2+ entry channel subtypes are expressed rarely or not at all in airway epithelia, epithelial cell models from other CF-relevant tissues, or vascular endothelia. Novel transient lipid transfection-mediated delivery of small interference RNA fragments specific to P2X4 and P2X6 (but not P2X5) into IB3-1 CF human airway epithelial cells inhibited extracellular zinc- and ATP-induced Ca2+ entry markedly in fura-2 Ca2+ measurements and "knocked down" protein by >65%. These data suggest that multiple P2X receptor Ca 2+ entry channel subtypes are expressed in airway epithelia. P2X 4 and P2X6 may coassemble on the airway surface as targets for possible therapeutics for CF independent of CFTR genotype.

Original languageEnglish
Pages (from-to)C388-C396
JournalAmerican Journal of Physiology - Cell Physiology
Volume289
Issue number2 58-2
DOIs
Publication statusPublished - Aug 1 2005

Keywords

  • Airway epithelia
  • Cystic fibrosis
  • Purinergic receptors
  • Therapy
  • Zinc receptors

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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