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Temperature and redox state dependence of native Kv2.1 currents in rat pancreatic -cells

Patrick E. MacDonald*, Anne Marie F. Salapatek* and Michael B. Wheeler*†

In pancreatic -cells, voltage-dependent K⁺ (Kv) channels repolarise glucose-stimulated action potentials. Kv channels are therefore negative regulators of Ca²⁺ entry and insulin secretion. We have recently demonstrated that Kv2.1 mediates the majority of -cell voltage-dependent outward K⁺ current and now investigate the function of native -cell Kv2.1 channels at near-physiological temperatures (32-35 °C). While -cell voltage-dependent outward K⁺ currents inactivated little at room temperature, both fast-inactivation (111.5 ± 14.3 ms) and slow-inactivation (1.21 ± 0.12 s) was observed at 32-35 °C. Kv2.1 mediates the fast-inactivating current observed at 32-35 °C, since it could be selectively ablated by expression of a dominant-negative Kv2.1 construct (Kv2.1N). The surprising ability of Kv2.1N to selectively remove the fast-inactivating component, together with its sensitivity to tetraethylammonium (TEA), demonstrate that this component is not mediated by the classically fast-inactivating and TEA-resistant channels such as Kv1.4 and 4.2. Increasing the intracellular redox state by elevating the cytosolic NADPH/NADP⁺ ratio from 1/10 to 10/1 increased the rates of both fast- and slow-inactivation. In addition, increasing the intracellular redox state also increased the relative contribution of the fast-inactivation component from 38.8 ± 2.1 % to 55.9 ± 1.8 %. The present study suggests that, in -cells, Kv2.1 channels mediate a fast-inactivating K⁺ current at physiological temperatures and may be regulated by the metabolic generation of NADPH.

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