F A C U L T Y P R O F I L E
ZHOU, MING, Ph.D.
Molecular physiology and biophysics of potassium channel modulations.
Modulation of Kv1 channels by cellular redox state and small-molecule compounds.
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. In a cell, Kv1 channels assemble with cytosolic beta subunit (Kvß) to form a stable complex. We have found that Kvß is a functional aldo-keto reductase, an enzyme that uses NADPH as cofactor to carry out a redox reaction. We have also found that Kvß’s enzymatic function is coupled to channel function: oxidation of Kvß-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 Kvß, for example, conversion of NADPH-to-NADP+, induces a large change in channel current, suggests that small-molecule compounds that bind to Kvß could regulate channel activity if the binding causes a structural change. The advantage of obtaining compounds that target Kvß 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 Kvß
Structural and functional studies of integral membrane proteins
Membrane proteins make up about ~30% of all proteins in our bodies, represent ~60% of drug targets, but constitute only 1% of all known structures. Atomic level structures of membrane proteins are essential for understanding mechanisms and obtaining small-molecule modulators. As part of the New York Consortium of Membrane Protein Structures (www.nycomps.org), we use a high throughput approach to clone and express membrane proteins for structural studies. Once a high resolution structure is obtained, then functional studies are initiated to test structure-based hypotheses.
Left panel: Kv1 channel (magenta) assembles with cytosolic Kvß subunit (green) to form a stable (Kv1)4-(Kvβ)4 complex (modified from Protein Data Bank entry 2A79). Each Kvß has an NADPH cofactor (orange) and an N terminus (blue) that closes the channel by the N-type inactivation mechanism. For clarity only two N termini are shown.
Right panel: Oxidation of the NADPH suppresses inactivation and increases channel current.
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