The Inhibitor of Connexin Cx36 Channels, Mefloquine, Inhibits Voltage-dependent Ca 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 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 channel activity, cytosolic Ca concentration ([Ca]) 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]. In the range of 5-50 μM mefloquine inhibited voltage-dependent Ca currents in primary beta cells as effectively as 1 μM nisoldipine, a specific blocker of L-type Ca channels. The Ca channel opening effect of Bay K8644 was completely antagonized by mefloquine. Likewise, the increase of [Ca] 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 channels and L-type Ca 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 mobilization, and the metabolic amplification by glucose permit a sustained rate of secretion.