Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 51, Pages E12043-E12052Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1811212115
Keywords
calcium channel; primary afferent; auxiliary subunit; N-type; trafficking
Categories
Funding
- Wellcome Trust Investigator Award [098360/Z/12/Z]
- Deutsche Forschungsgemeinschaft [FOR 2134 TP4]
- BIOSS-2 [A12]
- Wellcome Trust [098360/Z/12/Z] Funding Source: Wellcome Trust
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The auxiliary alpha(2)delta calcium channel subunits play key roles in voltage-gated calcium channel function. Independent of this, alpha(2)delta-1 has also been suggested to be important for synaptogenesis. Using an epitope-tagged knockin mouse strategy, we examined the effect of alpha(2)delta-1 on Ca(V)2.2 localization in the pain pathway in vivo, where Ca(V)2.2 is important for nociceptive transmission and alpha(2)delta-1 plays a critical role in neuropathic pain. We find Ca(V)2.2 is preferentially expressed on the plasma membrane of calcitonin gene-related peptide-positive small nociceptors. This is paralleled by strong presynaptic expression of Ca(V)2.2 in the superficial spinal cord dorsal horn. EM-immunogold localization shows Ca(V)2.2 predominantly in active zones of glomerular primary afferent terminals. Genetic ablation of alpha(2)delta-1 abolishes Ca(V)2.2 cell-surface expression in dorsal root ganglion neurons and dramatically reduces dorsal horn expression. There was no effect of alpha(2)delta-1 knockout on other dorsal horn pre- and postsynaptic markers, indicating the primary afferent pathways are not otherwise affected by alpha(2)delta-1 ablation.
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