The inhibitor of connexin Cx36 channels, mefloquine, inhibits voltage-dependent Ca2+ channels and insulin secretion

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, Ca2+ channel activity, cytosolic Ca2+ concentration ([Ca2+](i)) and insulin secretion. Mefloquine was tested in the concentration range of 5-50 mu M 25 mu M mefloquine was as effective as 500 mu M 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 [Ca2+](i). In the range of 5-50 mu M mefloquine inhibited voltage-dependent Ca2+ currents in primary beta cells as effectively as 1 mu M nisoldipine, a specific blocker of L-type Ca2+ channels. The Ca2+ channel opening effect of Bay K8644 was completely antagonized by mefloquine. Likewise, the increase of [Ca2+](i) and of insulin secretion stimulated by 40 mM KCI, but not that by 30 mM glucose was antagonized by 50 mu M mefloquine. Neither at 5 mu M nor at 50 mu M did mefloquin stimulate insulin secretion at basal glucose. In conclusion, mefloquine blocks K-ATP channels and L-type Ca2+ channels in pancreatic beta cells in the range from 5 to 50 mu M. Thus it inhibits depolarization-induced insulin secretion, but in the presence of a stimulatory glucose concentration additional effects of mefloquine, possibly on intracellular Ca2+ mobilization, and the metabolic amplification by glucose permit a sustained rate of secretion. (C) 2017 Elsevier B.V. All rights reserved.