Nieto-Rostro, M; Ramgoolam, K; Pratt, WS; Kulik, A; Dolphin, AC; (2018) Ablation of α_{2}δ-1 inhibits cell-surface trafficking of endogenous N-type calcium channels in the pain pathway in vivo. Proceedings of the National Academy of Sciences of the United States of America , 115 (51) E12043-E12052. 10.1073/pnas.1811212115.

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Abstract

The auxiliary α_{2}δ calcium channel subunits play key roles in voltage-gated calcium channel function. Independent of this, α_{2}δ-1 has also been suggested to be important for synaptogenesis. Using an epitope-tagged knockin mouse strategy, we examined the effect of α_{2}δ-1 on Ca_{V}2.2 localization in the pain pathway in vivo, where Ca_{V}2.2 is important for nociceptive transmission and α_{2}δ-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 α_{2}δ-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 α2δ-1 knockout on other dorsal horn pre- and postsynaptic markers, indicating the primary afferent pathways are not otherwise affected by α_{2}δ-1 ablation.

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