Mefloquine, a useful tool to investigate hemichannel function in pancreatic beta cells?

Background and aims: It is generally assumed that potassium depolarization leads to the same depolarization-induced insulin secretion as the closure of K_ATP channels. We have found, however, that it leads to a strong further increase when K_ATP channels were blocked by tolbutamide. This effect involves increases of the cytosolic Ca²⁺ concentration. It is unclear however, whether the Ca²⁺ influx occurs via voltage-dependent Ca²⁺ channels or via connexin Cx36 hemichannels which are known to be sensitive to potassium depolarization. The involvement of hemichannels is typically tested using mefloquine.

Methods: Membrane potential and currents were measured in the current clamp or voltage clamp mode, respectively of the patch-clamp technique, using cultured primary mouse beta cells (≤48h in RPMI 1640, 5 mM glucose).

Results: In the presence of 5 mM glucose mefloquine (5 – 50µM) depolarized the beta cell plasma membrane by about 15 mV without generation of action potentials. When tolbutamide depolarized the beta cell to a comparable extent, typical action potentials occurred. These could be inhibited by both 1µM nisoldipine, a specific blocker of L-type Ca²⁺ channels, and mefloquine. When mefloquine was applied before tolbutamide, tolbutamide was unable to generate action potentials. In voltage clamp experiments 50µM mefloquine suppressed Ca²⁺ currents comparable to the effect of nisoldipine.

Conclusion: In the same concentration range as it is used to affect hemichannels, mefloquine inhibits K_ATP channels (leading to depolarization) and L-type Ca²⁺ channels (suppressing action potentials) of the beta-cell. Thus, results obtained with this compound must be interpreted with caution.