Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Cell Rep. 2018 Feb 20;22(8):1956-1964. doi: 10.1016/j.celrep.2018.01.073.
Cavα2δ subunits contribute to the cell-surface expression of Cav2 calcium channels. Upregulation of Cavα2δ-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 Cavα2δ subunit. Coexpression of BK channels with the Cav2 calcium channels reduces their cell-surface expression and whole-cell current density by competing the Cavα2δ 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 Cavα2δ subunit with analgesic properties.
Cavα2δ 亚基有助于 Cav2 钙通道在细胞表面的表达。背根神经节神经元中的 Cavα2δ-1 在神经损伤后上调，导致脊髓背角中 Cav2.2 通道的突触丰富度增加，从而增强疼痛信号的传递。在这里，我们报告大电导钙激活钾 (BK) 通道与 Cavα2δ 亚基相互作用。BK 通道与 Cav2 钙通道共表达会通过将 Cavα2δ 亚基从 Cav2 复合物中竞争出来，从而降低其细胞表面表达和全细胞电流密度。生化分析表明，BK 通道的细胞外 N 端区域是这种效应的关键分子决定因素。鞘内递送至病毒构建体编码膜锚定 BK 通道 N 端肽可在炎症和神经性疼痛的小鼠模型中产生长期的镇痛作用。总的来说，我们的数据揭示了 Cavα2δ 亚基的一种具有镇痛特性的内源性配体。
