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INNOVATIVE METHODOLOGY

Modulation of epithelial Na⁺ channel activity by long-chain n–3 fatty acids

Physiology Department, Université Libre de Bruxelles, 1070 Brussels, Belgium

Submitted 10 March 2004 ; accepted in final form 8 June 2004

The epithelial sodium channel is found in apical membranes of a variety of native epithelial tissues, where it regulates sodium and fluid balance. In vivo, a number of hormones and other endogenous factors, including polyunsaturated fatty acids (PUFAs), regulate these channels. We tested the effects of essential n–3 and n–6 PUFAs on amiloride-sensitive sodium transport in A6 epithelial cells. Eicosapentaenoic acid [EPA; C20:5(n–3)] transiently stimulated amiloride-sensitive open-circuit current (I_Na) from 4.0 ± 0.3 to 7.7 ± 0.3 µA/cm² within 30 min (P < 0.001). No activation was seen in the presence of 10 µM amiloride. In cell-attached but not in cell-excised patches, EPA acutely increased the open probability of sodium channels from 0.45 ± 0.08 to 0.63 ± 0.10 (P = 0.02, paired t-test). n–6 PUFAs, including linoleic acid (C18:2), eicosatetraynoic acid (C20:4), and docosapentanoic acid (C22:5) had no effect, whereas n–3 docosahexanoic acid (C22:6) activated amiloride-sensitive I_Na in a manner similar to EPA. Activation of I_Na by EPA was prevented by H-89, a PKA inhibitor. Similarly, PKA activity was stimulated by EPA. Nonspecific stimulation of phosphodiesterase activity by CoCl₂ completely prevented the effect of EPA on sodium transport. We conclude that n–3 PUFAs activate epithelial sodium channels downstream of cAMP in a cAMP-dependent pathway also involving PKA.

patch clamp; epithelial sodium channel; PKA; A6 cells; amiloride

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