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Potassium Channel Subunit as Redox Sensor

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Science's STKE  06 Jun 2006:
Vol. 2006, Issue 338, pp. tw187
DOI: 10.1126/stke.3382006tw187

The Kvβ subunit of voltage-dependent potassium (Kv) channels has structural similarity to aldo-keto reductases (AKRs), enzymes that catalyze reduction of aldehyde groups to alcohols that are coupled to oxidation of an NADPH cofactor. However, it was unclear whether the Kvβ protein functioned in a catalytic capacity in its interaction with Kv channels, which allow voltage-sensitive conductance of potassium ions that is critical for action potentials in excitable cells. Weng et al. used spectrophotometric assays to show that purified rat Kvβ2 had associated NADPH and could reduce small-molecule aldehydes known to serve as substrates for other AKRs. Under other conditions, Kvβ2 could promote the reverse reaction--transfer of a hydride from an alcohol to reduce NADP+. Mutation of residues in the active site of the enzyme diminished the enzymatic activity. Application of a Kvβ substrate to Kv channels in inside-out patches from oocytes expressing the channel subunits decreased channel inactivation and increased peak current and steady-state current through the channel. The NADPH cofactor was very tightly associated with the channel, and proportional effects of various substrates on catalysis and channel function suggest that the conversion of bound NADPH to NADP+ may account for the altered properties of the channel. The results indicate that Kvβ may either be an enzyme whose function is modulated by channel activity or a redox sensor that could couple the redox state of the cell to Kv activity. Given that conductance of Kvβ channels is known to be altered in response to hypoxia or oxidative stress, the authors favor the latter possibility and anticipate that further elucidation of the interaction mechanism and identification of the physiological substrates of Kvβ should settle the matter once and for all.

J. Weng, Y. Cao, N. Moss, M. Zhou, Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase. J. Biol. Chem. 281, 15194-15200 (2006). [Abstract] [Full Text]

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