Mefloquine effects on the lens suggest cooperative gating of gap junction channels.

Mefloquine (MFQ) selectively blocks exogenously expressed gap junction channels composed of Cx50 but not Cx46. The purpose of the current study was to evaluate MFQ effects on wild-type (WT) mouse lenses that express both Cx50 and Cx46 in their outer shell of differentiating fibers (DFs). Lenses in which Cx46 was knocked into both Cx50 alleles (KI) were used as controls; MFQ had no effect on coupling in these lenses. When WT lenses were exposed to MFQ, the DF coupling conductance decreased significantly, suggesting that Cx50 contributes about 57% of the coupling conductance in DF and Cx46 contributes 43%. Remarkably, in the presence of MFQ, the 43% of the channels that remained open did not gate closed in response to a reduction in pH, whereas in the absence of MFQ, the same pH change caused all the DF channels to gate closed. Since MFQ is a selective blocker of Cx50 channels, it appears that Cx46 channels lack pH-mediated gating in the absence of functional Cx50 channels but are pH-sensitive in the presence of Cx50 channels. These results suggest the two types of channels interact and gate cooperatively.