Ablation of α 2 δ-1 inhibits cell-surface trafficking of endogenous N-type calcium channels in the pain pathway in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-12, Vol.115 (51), p.E12043
• Main Authors: Nieto-Rostro, Manuela, Ramgoolam, Krishma, Pratt, Wendy S, Kulik, Akos, Dolphin, Annette C
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1811212115

The auxiliary α δ calcium channel subunits play key roles in voltage-gated calcium channel function. Independent of this, α δ-1 has also been suggested to be important for synaptogenesis. Using an epitope-tagged knockin mouse strategy, we examined the effect of α δ-1 on Ca 2.2 localization in the pain pathway in vivo, where Ca 2.2 is important for nociceptive transmission and α δ-1 plays a critical role in neuropathic pain. We find Ca 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 2.2 in the superficial spinal cord dorsal horn. EM-immunogold localization shows Ca 2.2 predominantly in active zones of glomerular primary afferent terminals. Genetic ablation of α δ-1 abolishes Ca 2.2 cell-surface expression in dorsal root ganglion neurons and dramatically reduces dorsal horn expression. There was no effect of α δ-1 knockout on other dorsal horn pre- and postsynaptic markers, indicating the primary afferent pathways are not otherwise affected by α δ-1 ablation.