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Effect of hydrogen peroxide on ROMK channels in the cortical collecting duct

Department of Pharmacology, New York Medical College, Valhalla, New York

Submitted 29 September 2006 ; accepted in final form 7 December 2006

We used the patch-clamp technique to study the effect of H₂O₂ on the apical ROMK-like small-conductance K (SK) channel in the cortical collecting duct (CCD). The addition of H₂O₂ decreased the activity of the SK channels and the inhibitory effect of H₂O₂ was larger in the CCD from rats on a K-deficient diet than that from rats on a normal-K or a high-K diet. However, application of H₂O₂ did not inhibit the SK channels in inside-out patches. This suggests that the H₂O₂-mediated inhibition of SK channels was not due to direct oxidation of the SK channel protein. Because a previous study showed that H₂O₂ stimulated the expression of Src family protein tyrosine kinase (PTK) which inhibited SK channels (3), we explored the role of PTK in mediating the effect of H₂O₂ on SK channels. The application of H₂O₂ stimulated the activity of endogenous PTK in M-1 cells and increased tyrosine phosphorylation of ROMK in HEK293 cells transfected with GFP-ROMK1 and c-Src. However, blockade of PTK only attenuated but did not completely abolish the inhibitory effect of H₂O₂ on SK channels. Since H₂O₂ has also been demonstrated to activate mitogen-activated protein kinase, P38, and ERK (3), we examined the role of P38 and ERK in mediating the effect of H₂O₂ on SK channels. Similar to blockade of PTK, suppression of P38 and ERK did not completely abolish the H₂O₂-induced inhibition of SK channels. However, combined use of ERK, P38, and PTK inhibitors completely abolished the effect of H₂O₂ on SK channels. Also, treatment of the CCDs with concanavalin A, an agent which has been shown to inhibit endocytosis (19), abolished the inhibitory effect of H₂O₂. We conclude that addition of H₂O₂ inhibited SK channels by stimulating PTK activity, P38, and ERK in the CCD and that H₂O₂ enhances the internalization of the SK channels.

protein tyrosine kinase; P38; ERK; K secretion; superoxide anion

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