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Mutations in the extracellular loop of -rENaC alter sensitivity to amiloride and reactive species

¹Anesthesiology, ²Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35233; and ³Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Submitted 3 October 2003 ; accepted in final form 9 February 2004

We studied the effects of two mutations of the extracellular loop of the -subunit of the (ENaC) on amiloride-sensitive current in Xenopus laevis oocytes and the inhibition of this current by 3-morpholinosydnonimine (SIN-1). Injection of oocytes with wild-type (wt) -,-,-rENaC cRNA (8.3 ng/subunit) resulted 48–72 h later in inward Na⁺ currents (–5.5 ± 0.8 µA; means ± SE at –100 mV; n = 21), which were completely inhibited by amiloride. Oocytes injected with either _Y279A- or _Y283A- and -,-rENaC cRNAs had significantly lower Na⁺ currents. Furthermore, _Y279A-,-,-rENaC-injected oocytes had a higher K_i for amiloride (0.54 ± 0.97 vs. 0.10 ± 0.04 µM; P < 0.01). Exposure of oocytes to SIN-1 (1 mM) for 5 min decreased both total Na⁺ and amiloride-sensitive currents across wt and _Y279A- but not _Y283A-,-,-rENaC. Furthermore, exposure to SIN-1 increased the K_i for amiloride across wt but not _Y279A-,-,-rENaC-injected oocytes. These data indicate that both tyrosines are important for proper ENaC function and their oxidative modifications contribute to altered ENaC function.

peroxynitrite; tyrosines; 3-morpholinosydnonimine; Xenopus laevis oocytes; whole cell currents

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