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

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 i...

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Detalles Bibliográficos
Autores principales: Nieto-Rostro, Manuela, Ramgoolam, Krishma, Pratt, Wendy S., Kulik, Akos, Dolphin, Annette C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305000/
https://www.ncbi.nlm.nih.gov/pubmed/30487217
http://dx.doi.org/10.1073/pnas.1811212115
Descripción
Sumario: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 α(2)δ-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.