| Autor: |
Roe, Michael W., Worley, Jennings F., Qian, Feng, Tamarina, Natalia, Mittal, Anshu A., Dralyuk, Flora, Blair, Nathaniel T., Mertz, Robert J., Philipson, Louis H., Dukes, Iain D. |
| Zdroj: |
Journal of Biological Chemistry; April 1998, Vol. 273 Issue: 17 p10402-10410, 9p |
| Abstrakt: |
Although stimulation of insulin secretion by glucose is regulated by coupled oscillations of membrane potential and intracellular Ca2+([Ca2+] i), the membrane events regulating these oscillations are incompletely understood. In the presence of glucose and tetraethylammonium, transgenically derived β-cells (βTC3-neo) exhibit coupled voltage and [Ca2+] ioscillations strikingly similar to those observed in normal islets in response to glucose. Using these cells as a model system, we investigated the membrane conductance underlying these oscillations. Alterations in delayed rectifier or Ca2+-activated K+channels were excluded as a source of the conductance oscillations, as they are completely blocked by tetraethylammonium. ATP-sensitive K+channels were also excluded, since the ATP-sensitive K+channel blocker tolbutamide substituted for glucose in inducing [Ca2+] ioscillations. Thapsigargin, which depletes intracellular Ca2+stores, and maitotoxin, an activator of nonselective cation channels, both converted the glucose-dependent [Ca2+] ioscillations into a sustained elevation. On the other hand, both SKF 96365, a blocker of Ca2+store-operated channels, and external Na+removal suppressed the glucose-stimulated [Ca2+] ioscillations. Maitotoxin activated a nonselective cation current in βTC3 cells that was attenuated by removal of extracellular Na+and by SKF 96365, in the same manner to a current activated in mouse β-cells following depletion of intracellular Ca2+stores. Currents similar to these are produced by the mammalian trp-related channels, a gene family that includes Ca2+store-operated channels and inositol 1,4,5-trisphosphate-activated channels. We found several of the trpfamily genes were expressed in βTC3 cells by reverse transcriptase polymerase chain reaction using specific primers, but by Northern blot analysis, mtrp-4was the predominant message expressed. We conclude that a conductance underlying glucose-stimulated oscillations in β-cells is provided by a Ca2+store depletion-activated nonselective cation current, which is plausibly encoded by homologs of trpgenes. |
| Databáze: |
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