Altier Christophe, Dale Camila S, Kisilevsky Alexandra E, Chapman Kevin, Castiglioni Andrew J, Matthews Elizabeth A, Evans Rhian M, Dickenson Anthony H, Lipscombe Diane, Vergnolle Nathalie, Zamponi Gerald W
Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 1N4.
J Neurosci. 2007 Jun 13;27(24):6363-73. doi: 10.1523/JNEUROSCI.0307-07.2007.
N-type calcium channels are essential mediators of spinal nociceptive transmission. The core subunit of the N-type channel is encoded by a single gene, and multiple N-type channel isoforms can be generated by alternate splicing. In particular, cell-specific inclusion of an alternatively spliced exon 37a generates a novel form of the N-type channel that is highly enriched in nociceptive neurons and, as we show here, downregulated in a neuropathic pain model. Splice isoform-specific small interfering RNA silencing in vivo reveals that channels containing exon 37a are specifically required for mediating basal thermal nociception and for developing thermal and mechanical hyperalgesia during inflammatory and neuropathic pain. In contrast, both N-type channel isoforms (e37a- and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain.
N型钙通道是脊髓伤害性感受传递的重要介质。N型通道的核心亚基由单个基因编码，通过可变剪接可产生多种N型通道亚型。特别是，细胞特异性包含可变剪接的外显子37a会产生一种新型的N型通道，这种通道在伤害性神经元中高度富集，并且正如我们在此处所示，在神经性疼痛模型中表达下调。体内剪接异构体特异性小干扰RNA沉默表明，含有外显子37a的通道对于介导基础热痛觉以及在炎症性和神经性疼痛期间发展热痛觉过敏和机械性痛觉过敏是特别必需的。相比之下，两种N型通道亚型（含e37a和含e37b）均参与触觉性神经病理性异常性疼痛。因此，外显子37a充当分子开关，使通道在疼痛中发挥特定作用。
