Journal
CELL REPORTS
Volume 22, Issue 8, Pages 1956-1964Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.01.073
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Funding
- Natural Sciences and Engineering Research Council
- Alberta Innovates Health Solutions
- Vi Riddell Program for pediatric pain
- Savoy Foundation
- Canadian Institutes of Health Research
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Cav alpha 2 delta subunits contribute to the cell-surface expression of Cav2 calcium channels. Upregulation of Cav alpha 2 delta-1 in dorsal root ganglion neurons occurs after nerve injury and results in an increased synaptic abundance of Cav2.2 channels in the spinal dorsal horn, thus enhancing the transmission of pain signals. Here, we report that large conductance calcium-activated potassium (BK) channels interact with the Cav alpha 2 delta subunit. Coexpression of BK channels with the Cav2 calcium channels reduces their cell-surface expression and whole-cell current density by competing the Cav alpha 2 delta subunit away from the Cav2 complex. Biochemical analysis reveals that the extracellular N terminus region of the BK channel is the key molecular determinant of this effect. Intrathecally delivered virus constructs encoding a membrane-anchored BK channel N terminus peptide produces long-lasting analgesia in mouse models of inflammatory and neuropathic pain. Collectively, our data reveal an endogenous ligand of the Cav alpha 2 delta subunit with analgesic properties.
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