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Am J Physiol Cell Physiol (March 30, 2005). doi:10.1152/ajpcell.00491.2004
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Submitted on October 8, 2004
Accepted on March 22, 2005

RNA Interference Targeted to Multiple P2X Receptor Subtypes Attenuates Zinc-induced Calcium Entry

Lihua Liang1, Akos Zsembery1, and Erik M Schwiebert2*

1 Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
2 Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA

* To whom correspondence should be addressed. E-mail: eschwiebert{at}physiology.uab.edu.

A postulated therapeutic avenue in cystic fibrosis (CF) is activation of Ca2+-dependent Cl- channels via stimulation of Ca2+ 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. Based on these studies, the Ca2+ entry channels most likely involved were P2X purinergic receptor channels. In this study, molecular and biochemical data show co-expression of P2X4, P2X5, and P2X6 subtypes in non-CF (16HBE14o-) and CF (IB3-1) human bronchial epithelial cells. Other P2XR subtypes are rarely or not expressed in airway epithelia, epithelial cell models from other CF-relevant tissues, or in vascular endothelia. Novel transient lipid transfection-mediated delivery of small interference RNA (siRNA) 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 more than 65%. These data suggest that multiple P2X receptor Ca2+ entry channel subtypes are expressed in airway epithelia. P2X4 and P2X6 may co-assemble on the airway surface as targets for possible therapeutics for CF independent of CFTR genotype.




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