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Submitted on June 29, 2005
Accepted on July 29, 2005
-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in 
-Cells
From Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany; Bartholin Instituttet, Rigshospitalet, DK-2100 Copenhagen, Denmark; Department of Cell Physiology and Metabolism, University Medical Center, 1211 Geneva 4, Switzerland
* To whom correspondence should be addressed. E-mail: gromada{at}lilly.com.
In isolated rat pancreatic 
-cells, glucose, arginine and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P < 0.05; n = 5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP-channels. The N-type Ca2+-channel blocker 
-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+-channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. -conotoxin suppressed glucagon release to 15 mM K+, whereas a combination of -conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mM K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments exocytosis was stimulated by reducing the cytoplasmic ADP concentration whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat -cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+-channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated -cells contrasts to the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.
-cell •
ATP-sensitive K+-channel
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