Abstract
A truncated form of the ATP release channel pannexin 1 (Panx1), Panx1 1–89 , 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 Panx1 1–89 on its own (without the presence of wtPanx1) mediates ATP release has not been tested. Here, we show that Panx1 1–89 by 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 Panx1 1–89 peptide. Thus, augmenting extracellular potassium ion concentrations enhances Panx1 1–89 -mediated conductance. Moreover, despite the severe truncation, Panx1 1–89 retains 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 Panx1 1–89 mutant should facilitate structure-function analysis of Panx1 channels.
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