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J. Biol. Chem., Vol. 281, Issue 48, 36960-36968, December 1, 2006

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Interregulation of Proton-gated Na⁺ Channel 3 and Cystic Fibrosis Transmembrane Conductance Regulator^*

Xuefeng Su, Qingnan Li, Kedar Shrestha, Estelle Cormet-Boyaka, Lan Chen, Peter R. Smith, Eric J. Sorscher^¶||, Dale J. Benos^¶, Sadis Matalon, and Hong-Long Ji¹

From the Department of Anesthesiology, Physiology, and Biophysics, ^||Medicine, and the ^¶Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35205

Proton-gated Na⁺ channels (ASIC) are new members of the epithelial sodium channel/degenerin gene family. ASIC3 mRNA has been detected in the homogenate of pulmonary tissues. However, whether ASIC3 is expressed in the apical membranes of lung epithelial cells and whether it regulates cystic fibrosis transmembrane conductance regulator (CFTR) function are not known at the present time. Using reverse transcription-PCR, we found that the ASIC3 mRNA was expressed in the human airway mucosal gland (Calu-3) and human airway epithelial (16HBE14o) cells. Indirect immunofluorescence microscopy revealed that ASIC3 was co-segregated with CFTR in the apical membranes of Calu-3 cells. Proton-gated, amiloride-sensitive short circuit Na⁺ currents were recorded across Calu-3 monolayers mounted in an Ussing chamber. In whole-cell patch clamp studies, activation of CFTR channels with cAMP reduced proton-gated Na⁺ current in Calu-3 cells from -154 ± 28 to -33 ± 16 pA (n = 5, p < 0.05) at -100 mV. On the other hand, cAMP-activated CFTR activity was significantly inhibited following constitutive activation of putative ASIC3 at pH 6.0. Immunoassays showed that both ASIC3 and CFTR proteins were expressed and co-immunoprecipitated mutually in Calu-3 cells. Similar results were obtained in human embryonic kidney 293T cells following transient co-transfection of ASIC3 and CFTR. Our results indicate that putative CFTR and ASIC3 channels functionally interact with each other, possibly via an intermolecular association. Because acidic luminal fluid in the cystic fibrosis airway and lung tends to stimulate ASIC3 channel expression and activity, the interaction of ASIC3 and CFTR may contribute to defective salt and fluid transepithelial transport in the cystic fibrotic pulmonary system.

Received for publication, August 21, 2006 , and in revised form, September 22, 2006.

^* This work was supported by Cystic Fibrosis Foundation Grants JI04G0, DK37206, DK53090, DK56596, DK054781, R464-CR02, HL31197, and HL51173. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology, Uniiversity of Alabama at Birmingham, 901 19th St. South, 232 BMR2, Birmingham, AL 35205-3703. Fax: 205-934-7437; E-mail: hlji{at}uab.edu.

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