A metastasis-associated Pannexin1 mutant (Panx11-89) forms a minimalist ATP release channel

Abstract

AbstractA truncated form of the ATP release channel pannexin 1 (Panx1), Panx11–89, is enriched in metastatic breast cancer cells and has been proposed to mediate metastatic cell survival by increasing ATP release through mechanosensitive Panx1 channels. However, whether Panx11–89on its own (without the presence of wtPanx1) mediates ATP release has not been tested. Here, we show that Panx11–89by itself can form a constitutively active membrane channel, capable of releasing ATP even in the absence of wild type Panx1. Our biophysical characterization reveals that most basic structure-function features of the channel pore are conserved in the truncated Panx11–89peptide. Thus, augmenting extracellular potassium ion concentrations enhances Panx11–89-mediated conductance. Moreover, despite the severe truncation, Panx11–89retains the sensitivity to most of wtPanx1 channel inhibitors and can thus be targeted. Therefore, Panx1 blockers have the potential to be of therapeutic value to combat metastatic cell survival. Our study not only elucidates a mechanism for ATP release from cancer cells, but it also supports that the Panx11–89mutant should facilitate structure-function analysis of Panx1 channels.