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Acute application of TNF stimulates apical 70-pS K⁺ channels in the thick ascending limb of rat kidney

Department of Pharmacology, New York Medical College, Valhalla, New York 10595

Submitted 17 March 2003 ; accepted in final form 19 May 2003

TNF has been shown to be synthesized by the medullary thick ascending limb (mTAL) (21). In the present study, we used the patch-clamp technique to study the acute effect of TNF on the apical 70-pS K⁺ channel in the mTAL. Addition of TNF (10 nM) significantly stimulated activity of the 70-pS K⁺ channel and increased NP_o [a product of channel open probability (P_o) and channel number (N)] from 0.20 to 0.97. The stimulatory effect of TNF was observed only in cell-attached patches but not in excised patches. Moreover, addition of TNF had no effect on the ROMK-like small-conductance K⁺ channels in the TAL. The dose-response curve of the TNF effect yielded a K_m value of 1 nM, a concentration that increased channel activity to 50% maximal stimulatory effect of TNF. The concentrations required for reaching the plateau of the TNF effect were between 5 and 10 nM. The stimulatory effect of TNF on the 70-pS K⁺ channel was observed in the presence of N-nitro-L-arginine methyl ester. This indicated that the effect of TNF was not mediated by a nitric oxide-dependent pathway. Also, inhibition of PKA did not affect the stimulatory effect of TNF. In contrast, inhibition of protein tyrosine kinase not only increased activity of the 70-pS K⁺ channel but also abolished the effect of TNF. Moreover, inhibition of protein tyrosine phosphatase (PTP) blocked the stimulatory effect of TNF on the 70-pS K⁺ channel. The notion that the TNF effect results from stimulation of PTP activity is supported by PTP activity assay in which treatment of mTAL cells with TNF significantly increased the activity of PTP. We conclude that TNF stimulates the 70-pS K⁺ channel via stimulation of PTP in the mTAL.

ROMK channel; protein tyrosine kinase; protein tyrosine phosphatase; N^G-nitro-L-arginine methyl ester

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