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¹ Molecular Metabolism² Islet Cell Exocytosis, Department of Clinical Science, Clinical Research Center, SE-205 02 Malmö, Sweden³ Lund University Diabetes Center, Malmö, Sweden

(Correspondence should be addressed to M D Nitert who is now at Unit of Molecular Metabolism, Department of Clinical Science, CRC Floor 12, SE-205 02 Malmö, Sweden; Email: marloes.dekker_nitert{at}med.lu.se)

In clonal β-cell lines and islets from different species, a variety of calcium channels are coupled to glucose-stimulated insulin secretion. The aim of this study was to identify the voltage-gated calcium channels that control insulin secretion in insulinoma (INS)-1 832/13 cells. The mRNA level of Ca_V1.2 exceeded that of Ca_V1.3 and Ca_V2.3 two-fold. Insulin secretion, which rose tenfold in response to 16.7 mM glucose, was completely abolished by 5 µM isradipine that blocks Ca_V1.2 and Ca_V1.3. Similarly, the increase in intracellular calcium in response to 15 mM glucose was decreased in the presence of 5 µM isradipine, and the frequency of calcium spikes was decreased to the level seen at 2.8 mM glucose. By contrast, inhibition of Ca_V2.3 with 100 nM SNX-482 did not significantly affect insulin secretion or intracellular calcium. Using RNA interference, Ca_V1.2 mRNA and protein levels were knocked down by 65% and 34% respectively, which reduced insulin secretion in response to 16.7 mM glucose by 50%. Similar reductions in calcium currents and cell capacitance were seen in standard whole-cell patch-clamp experiments. The remaining secretion of insulin could be reduced to the basal level by 5 µM isradipine. Calcium influx underlying this residual insulin secretion could result from persisting Ca_V1.2 expression in transfected cells since knock-down of Ca_V1.3 did not affect glucose-stimulated insulin secretion. In summary, our results suggest that Ca_V1.2 is critical for insulin secretion in INS-1 832/13 cells.

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