Differential regulation of Connexin50 and Connexin46 by PI3K signaling

•Inhibition of PI3K signaling reduces Cx50 gap junctional conductance.•Constitutive activation of PI3K signaling increases Cx50-mediated coupling.•Cx46 conductance levels are not regulated by PI3K signaling.

Gap junction channels can modify their activity in response to cell signaling pathways. Here, we demonstrate that Connexin50 (Cx50) coupling, but not Connexin46 (Cx46), increased when co-expressed with a constitutively active p110α subunit of PI3K in Xenopus oocytes. In addition, inhibition of PI3K signaling by blocking p110α, or Akt, significantly decreased gap junctional conductance in Cx50 transfected HeLa cells, with no effect on Cx46. Alterations in coupling levels were not a result of reduced Cx50 unitary conductance, suggesting that changes in the number of active channels were responsible. These data indicate that Cx50 is specifically regulated by the PI3K signaling pathway.