Potent block of Cx36 and Cx50 gap junction channels by mefloquine

Abstract

Recently, great interest has been shown in understanding the functional roles of specific gap junction proteins (connexins) in brain, lens, retina, and elsewhere. Some progress has been made by studying knockout mice with targeted connexin deletions. For example, such studies have implicated the gap junction protein Cx36 in synchronizing rhythmic activity of neurons in several brain regions. Although knockout strategies are informative, they can be problematic, because compensatory changes sometimes occur during development. Therefore, it would be extremely useful to have pharmacological agents that block specific connexins, without major effects on other gap junctions or membrane channels. We show that mefloquine, an antimalarial drug, is one such agent. It blocked Cx36 channels, expressed in transfected N2A neuroblastoma cells, at low concentrations (IC 50 Ϸ 300 nM). Mefloquine also blocked channels formed by the lens gap junction protein, Cx50 (IC50 Ϸ 1.1 M). However, other gap junctions (e.g., Cx43, Cx32, and Cx26) were only affected at concentrations 10-to 100-fold higher. To further examine the utility and specificity of this compound, we characterized its effects in acute brain slices. Mefloquine, at 25 M, blocked gap junctional coupling between interneurons in neocortical slices, with minimal nonspecific actions. At this concentration, the only major side effect was an increase in spontaneous synaptic activity. Mefloquine (25 M) caused no significant change in evoked excitatory or inhibitory postsynaptic potentials, and intrinsic cellular properties were also mostly unaffected. Thus, mefloquine is expected to be a useful tool to study the functional roles of Cx36 and Cx50.

Protection of retinal cells from ischemia by a novel gap junction inhibitor

“…During the synthesis of PQ1 several intermediates were tested and compared to mefloquine, a known gap junction inhibitor [18,19]. Gap junction dye transfer of Lucifer yellow was measured and results are shown in Fig.…”

“…Previously the anti-malarial chloroquine drugs, such as mefloquine, have been reported to be potent inhibitors of the gap junction protein, Cx50 [18,19]. Based on simulated docking studies using this class of substituted quinolines, several structures were found to dock into the channel pore of Cx43.…”

Structural and Functional Similarities of Calcium Homeostasis Modulator 1 (CALHM1) Ion Channel with Connexins, Pannexins, and Innexins*

“…C, plot of relative permeability of each cation versus its respective ionic radius. tors of pannexins (32), and specific members of the connexin family (33)(34)(35), respectively. None of these compounds inhibited CALHM1 currents (Fig.…”

Evidence for sustained ATP release from liver cells that is not mediated by vesicular exocytosis

“…Similar to CBX, mefloquine also inhibits certain connexin hemichannels [32]. Consequently, to assess whether connexin channels contribute to sustained ATP release, luminescence was measured from HTC cells in the presence of FFA, a potent blocker of connexin channels.…”