A metastasis-associated pannexin-1 mutant (Panx1(1-89)) forms a minimalist ATP release channel.

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 wild-type Panx1 (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 wtPanx1. Our biophysical characterization reveals that most basic structure-function features of the channel pore are conserved in the truncated Panx1(1-89) polypeptide. Thus, augmenting extracellular potassium ion concentrations enhances Panx1(1-89)-mediated conductance. Moreover, despite the severe truncation, Panx1(1-89) retains sensitivity to most wtPanx1 channel inhibitors. Therefore, Panx1 blockers may be of therapeutic value to combat metastatic cell survival. Our study both provides a mechanism for ATP release from cancer cells and suggests that Panx1(1-89) might aid in the structure-function analysis of Panx1 channels.