Comparison of the effects of perchlorate and Bay K 8644 on the dynamics of cytoplasmic Ca2+ concentration and insulin secretion in mouse beta-cells.
Non-inbred ob/ob mice were used to study the dynamics of cytoplasmic Ca2+ concentration ([Ca2+]i) in isolated pancreatic beta-cells using microfluorimetry with fura 2/AM as probe, and the dynamics of insulin secretion in isolated pancreatic islets. D-Glucose (20 mM) caused a transient peak increase in [CA2+]i which changed to either an oscillating or a flat, elevated phase. The lag-time before the first peak increase in [Ca2+]i was markedly shortened by 12 mM ClO4- and the glucose-stimulated level of [Ca2+]i after the first peak was clearly elevated by the anion. ClO4- did not change the basal [Ca2+]i at 3 mM glucose. Extracellular Ca2+ deficiency abolished the effect of high glucose and ClO4- on [Ca2+]i. This suggests that ClO4- acts as an amplifier of transmembrane Ca2+ inflow. The L-type Ca2+ channel agonist, Bay K 8644 (0.01-1.0 microM), strictly reproduced all the effects of perchlorate on the glucose-stimulated beta-cell [Ca2+]i. Both phases of insulin release (20 mM glucose) were markedly enhanced by ClO4- (12 mM) or Bay K 8644 (1.0 microM). The lag-time for glucose-stimulated insulin release was shortened by both agents. Taken together, these data strengthen the idea that perchlorate amplifies the glucose-stimulation of [Ca2+]i and insulin release by directly modifying the function of the L-type Ca2+ channel. This effect can induce both a more prompt onset of and an amplified level of beta-cell secretory activity.
Larsson-Nyrén
G
G
Department of Histology and Cell Biology, Umeå University, Sweden.
Sehlin
J
J
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type; D005260:Female; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008820:Mice, Obese; D010472:Perchlorates / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D017670:Sodium Compounds / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D007328:Insulin; D010472:Perchlorates; D017670:Sodium Compounds; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C031068:sodium perchlorate; D005947:Glucose; D011188:Potassium; D002118:Calcium