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Tytuł:
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The inhibitor of connexin Cx36 channels, mefloquine, inhibits voltage-dependent Ca channels and insulin secretion.
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Autorzy:
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Seemann N; Institute of Pharmacology and Toxicology, Technische Universität Braunschweig, D-38106 Braunschweig, Germany.
Welling A; Institute of Pharmacology and Toxicology, Technische Universität München, D-80802 München, Germany.
Rustenbeck I; Institute of Pharmacology and Toxicology, Technische Universität Braunschweig, D-38106 Braunschweig, Germany. Electronic address: .
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Źródło:
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Molecular and cellular endocrinology [Mol Cell Endocrinol] 2018 Sep 05; Vol. 472, pp. 97-106. Date of Electronic Publication: 2017 Dec 05.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Limerick : North Holland Publishing
Original Publication: Amsterdam, North-Holland.
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MeSH Terms:
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Calcium Channels/*metabolism
Connexins/*antagonists & inhibitors
Insulin Secretion/*drug effects
Mefloquine/*pharmacology
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology ; Action Potentials/drug effects ; Animals ; Calcium/metabolism ; Calcium Channel Blockers/pharmacology ; Connexins/metabolism ; Dihydropyridines/pharmacology ; Glucose/pharmacology ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Ion Channel Gating/drug effects ; Mice ; Nisoldipine/pharmacology ; Potassium Chloride/pharmacology ; Tolbutamide/pharmacology ; Gap Junction delta-2 Protein
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Contributed Indexing:
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Keywords: Connexin hemichannels; Insulin secretion; K(ATP) channels; L-type Ca(2+) channels; Mefloquine
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Substance Nomenclature:
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0 (Calcium Channel Blockers)
0 (Calcium Channels)
0 (Connexins)
0 (Dihydropyridines)
4I8HAB65SZ (Nisoldipine)
660YQ98I10 (Potassium Chloride)
71145-03-4 (3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester)
7M8K3P6I89 (1,4-dihydropyridine)
982XCM1FOI (Tolbutamide)
IY9XDZ35W2 (Glucose)
SY7Q814VUP (Calcium)
TML814419R (Mefloquine)
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Entry Date(s):
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Date Created: 20171207 Date Completed: 20190422 Latest Revision: 20231213
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Update Code:
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20240105
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DOI:
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10.1016/j.mce.2017.11.024
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PMID:
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29208420
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The antimalarial agent, mefloquine, inhibits the function of connexin Cx36 gap junctions and hemichannels and has thus become a tool to investigate their physiological relevance in pancreatic islets. In view of earlier reports on a K ATP channel-block by mefloquine, the specificity of mefloquine as a pharmacological tool was investigated. Mouse pancreatic islets and single beta cells were used to measure membrane potential, whole cell currents, Ca 2+ channel activity, cytosolic Ca 2+ concentration ([Ca 2+ ] i ) and insulin secretion. Mefloquine was tested in the concentration range of 5-50 μM 25 μM mefloquine was as effective as 500 μM tolbutamide to depolarize the plasma membrane of beta cells, but did not induce action potentials. Rather, it abolished tolbutamide-induced action potentials and the associated increase of [Ca 2+ ] i . In the range of 5-50 μM mefloquine inhibited voltage-dependent Ca 2+ currents in primary beta cells as effectively as 1 μM nisoldipine, a specific blocker of L-type Ca 2+ channels. The Ca 2+ channel opening effect of Bay K8644 was completely antagonized by mefloquine. Likewise, the increase of [Ca 2+ ] i and of insulin secretion stimulated by 40 mM KCl, but not that by 30 mM glucose was antagonized by 50 μM mefloquine. Neither at 5 μM nor at 50 μM did mefloquin stimulate insulin secretion at basal glucose. In conclusion, mefloquine blocks K ATP channels and L-type Ca 2+ channels in pancreatic beta cells in the range from 5 to 50 μM. Thus it inhibits depolarization-induced insulin secretion, but in the presence of a stimulatory glucose concentration additional effects of mefloquine, possibly on intracellular Ca 2+ mobilization, and the metabolic amplification by glucose permit a sustained rate of secretion.
(Copyright © 2017 Elsevier B.V. All rights reserved.)