PT  - JOURNAL ARTICLE
AU  - Minae Yoshida
AU  - Dean Willis
TI  - Evidence for a role for BK channels in the regulation of ADAM17 activity
AID  - 10.1101/811000
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 811000
4099  - http://biorxiv.org/content/early/2019/10/19/811000.short
4100  - http://biorxiv.org/content/early/2019/10/19/811000.full
AB  - Large-conductance voltage and calcium activated channels, KCa1.1, have a large single conductance (~p250) and are highly selective for potassium ions. As a result they have been termed big potassium channels (BK channels). Because of the channel’s ability to integrate multiple physical and chemical signals they have received much attention in excitable cells. In comparison they have received relatively little attention in non-excitable cells in those of the immune system. Here we report evidence that the BK channel regulates ADAM17 activity. Upon macrophage activation, BK channels translocate to the cell membrane. Genetic or pharmacological inhibition of the cell membrane BK channels resulted in elevated TNF-α release and increased metalloproteinase a disintegrin and metalloproteinase domain 17 (ADAM17) activity. Inhibitors of BK channels also increased IL-6Rα release, a second ADAM17 substrate. In comparison, a BK channel opener decreases TNF-α release. Taken together, our results demonstrate a novel mechanism by which ion channel regulates ADAM17 activity. Given the broad range of ADAM17 substrates, this finding has implications in many fields of cell biology including immunology, neurology and cancer biology.