Ming Zhou, Ph.D.

Research

The Shaker family voltage-dependent potassium channels (Kv1) are expressed in a wide variety of cells and essential for cellular excitability. In humans, loss-of-function mutations of Kv1 channels lead to hyperexcitability and are directly linked to episodic ataxia and atrial fibrillation. We have found that Kvfl is a functional aldo-keto reductase, an enzyme that uses NADPH as cofactor to carry out a redox reaction. We have also found that Kvfl's enzymatic function is coupled to channel function: oxidation of Kvfl-bound NADPH induces a large increase in channel current. Coupling between NADPH oxidation and channel activity provides a molecular basis for how excitability of a cell may be regulated by changes in cellular redox state or oxygen levels. Furthermore, that a small structural change on Kvfl, for example, conversion of NADPH-to-NADP+, induces a large change in channel current, suggests that small-molecule compounds that bind to Kvfl could regulate channel activity if the binding causes a structural change. The advantage of obtaining compounds that target Kvfl is that these compounds will be specific to only the Kv1 channels because of the exclusive assembly between the two. There are two lines of research currently ongoing. 1. To understand mechanism of Kv1 channel modulation by cellular redox states 2. To achieve pharmacological control of Kv1 channel by targeting Kvfl.