Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase

The beta subunit (Kv beta) of the Shaker family voltage-dependent potassium channels (Kv1) is a cytosolic protein that forms a permanent complex with the channel. Sequence and structural conservation indicates that Kv beta resembles an aldo-keto reductase (AKR), an enzyme that catalyzes a redox reaction using an NADPH cofactor. A putative AKR in complex with a Kv channel has led to the hypothesis that intracellular redox potential may dynamically influence the excitability of a cell through Kv beta. Since the AKR function of Kv beta has never been demonstrated, a direct functional coupling between the two has not been established. We report here the identification of Kv beta substrates and the demonstration that Kv beta is a functional AKR. We have also found that channel function is modulated when the Kv beta-bound NADPH is oxidized. Further studies of the enzymatic properties of Kv beta seem to favor the role of Kv beta as a redox sensor. These results suggest that Kv beta may couple the excitability of the cell to its metabolic state and present a new avenue of research that may lead to understanding of the physiological functions of Kv beta.