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Pancreatic β-cells are equipped with voltage-gated Na+channels that undergo biphasic voltage-dependent steady-state inactivation. A small Na+current component (10-15%) inactivates over physiological membrane potentials and contributes to action potential firing. However, the major Na+channel component is completely inactivated at -90 to -80 mV and is therefore inactive in the β-cell. It has been proposed that the biphasic inactivation reflects the contribution of different NaVα-subunits. We tested this possibility by expression of TTX-resistant variants of the NaVsubunits found in β-cells (NaV1.3, NaV1.6 and NaV1.7) in insulin-secreting Ins1 cells and in non-β-cells (including HEK and CHO cells). We found that all NaVsubunits inactivated at 20-30 mV more negative membrane potentials in Ins1 cells than in HEK or CHO cells. The more negative inactivation in Ins1 cells does not involve a diffusible intracellular factor because the difference between Ins1 and CHO persisted after excision of the membrane. NaV1.7 inactivated at 15--20 mV more negative membrane potentials than NaV1.3 and NaV1.6 in Ins1 cells but this small difference is insufficient to solely explain the biphasic inactivation in Ins1 cells. In Ins1 cells, but never in the other cell types, widely different components of NaVinactivation (separated by 30 mV) were also observed following expression of a single type of NaVα-subunit. The more positive component exhibited a voltage-dependence of inactivation similar to that found in HEK/CHO cells. We propose that biphasic NaVinactivation in insulin-secreting cells reflects insertion of channels in membrane domains that differ with regard to lipid and/or membrane protein composition. This article is protected by copyright. All rights reserved.

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Journal article


J Physiol

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