Enhanced Glucose Tolerance by SK4 Channel Inhibition in Pancreatic β-Cells
| Autor: | Daniela Wolpers, Martina Düfer, Peter Krippeit-Drews, Gisela Drews, Peter Ruth, Belinda Gier |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Blood Glucose
Male medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Mice Inbred Strains Biology Models Biological Membrane Potentials Mice In vivo Biological Clocks Internal medicine Insulin-Secreting Cells Internal Medicine medicine Animals Channel blocker Crosses Genetic Membrane potential Mice Knockout Glucose tolerance test medicine.diagnostic_test Insulin Membrane hyperpolarization Glucose Tolerance Test Intermediate-Conductance Calcium-Activated Potassium Channels Mice Inbred C57BL Electrophysiology Endocrinology Islet Studies Female Original Article Signal transduction |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE Ca2+-regulated K+ channels are involved in numerous Ca2+-dependent signaling pathways. In this study, we investigated whether the Ca2+-activated K+ channel of intermediate conductance SK4 (KCa3.1, IK1) plays a physiological role in pancreatic β-cell function. RESEARCH DESIGN AND METHODS Glucose tolerance and insulin sensitivity were determined in wild-type (WT) or SK4 knockout (SK4-KO) mice. Electrophysiological experiments were performed with the patch-clamp technique. The cytosolic Ca2+ concentration ([Ca2+]c) was determined by fura-2 fluorescence. Insulin release was assessed by radioimmunoassay, and SK4 protein was detected by Western blot analysis. RESULTS SK4-KO mice showed improved glucose tolerance, whereas insulin sensitivity was not altered. The animals were not hypoglycemic. Isolated SK4-KO β-cells stimulated with 15 mmol/l glucose had an increased Ca2+ action potential frequency, and single-action potentials were broadened. These alterations were coupled to increased [Ca2+]c. In addition, glucose responsiveness of membrane potential, [Ca2+]c, and insulin secretion were shifted to lower glucose concentrations. SK4 protein was expressed in WT islets. An increase in K+ currents and concomitant membrane hyperpolarization could be evoked in WT β-cells by the SK4 channel opener DCEBIO (100 μmol/l). Accordingly, the SK4 channel blocker TRAM-34 (1 μmol/l) partly inhibited KCa currents and induced electrical activity at a threshold glucose concentration. In stimulated WT β-cells, TRAM-34 further increased [Ca2+]c and broadened action potentials similar to those seen in SK4-KO β-cells. SK4 channels were found to substantially contribute to Kslow (slowly activating K+ current). CONCLUSIONS SK4 channels are involved in β-cell stimulus-secretion coupling. Deficiency of SK4 current induces elevated β-cell responsiveness and coincides with improved glucose tolerance in vivo. Therefore, pharmacologic modulation of these channels might provide an interesting approach for the development of novel insulinotropic drugs. |
| Databáze: | OpenAIRE |
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