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Redox State and Potassium Channel Activity: the Missing Link

Aldo-keto reductases catalyze redox reactions using NADPH as a cofactor, turning aldehydes into alcohols. It has been known for some time that Kv, a subunit associated with Kv potassium channels, has structural elements characteristic of aldo-keto reductases, but whether it serves this enzymatic function has not previously been demonstrated. Further support for this theory comes from the observation that changes in Kv channel current occur when the redox state is altered. Could Kv be the missing link between cellular redox chemistry and Kv channel activities?

Kv resembles an aldo-keto reductase.

Jun Weng and colleagues show that the answer to this question is yes, in this Paper of the Week. The researchers identified several Kv substrates and demonstrated that Kv is a functional aldo-keto reductase. They also found that channel function is modulated when the Kv-bound NADPH is oxidized. This study is the first to show that Kv subunits have aldo-keto reductase activity and that this activity is responsible for the modulation of Kv channel gating properties by subunits. More importantly, the aldo-keto reductase activity of subunits represents the functional link between the redox state of the cell and potassium channel activity that regulates membrane excitability.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 15194–15200

Sweetly Controlling Glutamate Oxidation

Congenital hyperinsulinism (HI) is a group of disorders that cause hypoglycemia in infants and children. The majority of these cases appears to be due to genetic defects in the regulation of insulin secretion by pancreatic -cells. For example, children with mutations in glutamate dehydrogenase (GDH) experience a hyperinsulinism-hyperammonemia syndrome (GDH-HI), and their -cells are sensitized to leucine stimulation.

To increase understanding of the role of GDH in insulin secretion, Changhong Li and colleagues generated GDH transgenic mice that expressed in islets the mutant human GDH-HI H454Y and human wild-type GDH with the rat insulin promoter. The H454Y GDH transgenic mice had hypoglycemia, confirming that the H454Y mutation can cause disease. Enhancement of insulin release by the H454Y GDH mutation or by leucine activation was associated with increased oxidative deamination of glutamate via GDH. These results confirm that in mouse islets GDH functions predominantly in the direction of glutamate oxidation rather than glutamate synthesis, and this flux is tightly controlled by glucose.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 15064–15072

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