Yang Li, Stephens Gary J
School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AJ, United Kingdom.
Cell Calcium. 2009 Oct;46(4):248-56. doi: 10.1016/j.ceca.2009.08.001. Epub 2009 Sep 1.
Voltage-dependent Ca(2+) channels (VDCCs) have emerged as targets to treat neuropathic pain; however, amongst VDCCs, the precise role of the Ca(V)2.3 subtype in nociception remains unproven. Here, we investigate the effects of partial sciatic nerve ligation (PSNL) on Ca(2+) currents in small/medium diameter dorsal root ganglia (DRG) neurones isolated from Ca(V)2.3(-/-) knock-out and wild-type (WT) mice. DRG neurones from Ca(V)2.3(-/-) mice had significantly reduced sensitivity to SNX-482 versus WT mice. DRGs from Ca(V)2.3(-/-) mice also had increased sensitivity to the Ca(V)2.2 VDCC blocker omega-conotoxin. In WT mice, PSNL caused a significant increase in omega-conotoxin-sensitivity and a reduction in SNX-482-sensitivity. In Ca(V)2.3(-/-) mice, PSNL caused a significant reduction in omega-conotoxin-sensitivity and an increase in nifedipine sensitivity. PSNL-induced changes in Ca(2+) current were not accompanied by effects on voltage-dependence of activation in either Ca(V)2.3(-/-) or WT mice. These data suggest that Ca(V)2.3 subunits contribute, but do not fully underlie, drug-resistant (R-type) Ca(2+) current in these cells. In WT mice, PSNL caused adaptive changes in Ca(V)2.2- and Ca(V)2.3-mediated Ca(2+) currents, supporting roles for these VDCCs in nociception during neuropathy. In Ca(V)2.3(-/-) mice, PSNL-induced changes in Ca(V)1 and Ca(V)2.2 Ca(2+) current, consistent with alternative adaptive mechanisms occurring in the absence of Ca(V)2.3 subunits.
电压依赖性钙通道（VDCCs）已成为治疗神经性疼痛的靶点；然而，在VDCCs中，Ca(V)2.3亚型在伤害感受中的精确作用仍未得到证实。在此，我们研究了部分坐骨神经结扎（PSNL）对从小/中直径背根神经节（DRG）神经元分离出的Ca(2+)电流的影响，这些神经元来自Ca(V)2.3(-/-)基因敲除小鼠和野生型（WT）小鼠。与WT小鼠相比，Ca(V)2.3(-/-)小鼠的DRG神经元对SNX-482的敏感性显著降低。Ca(V)2.3(-/-)小鼠的DRG对Ca(V)2.2 VDCC阻滞剂ω-芋螺毒素的敏感性也增加。在WT小鼠中，PSNL导致ω-芋螺毒素敏感性显著增加，而SNX-482敏感性降低。在Ca(V)2.3(-/-)小鼠中，PSNL导致ω-芋螺毒素敏感性显著降低，硝苯地平敏感性增加。PSNL诱导的Ca(2+)电流变化在Ca(V)2.3(-/-)或WT小鼠中均未伴随着对激活电压依赖性的影响。这些数据表明，Ca(V)2.3亚基对这些细胞中的耐药性（R型）Ca(2+)电流有贡献，但并非完全是其基础。在WT小鼠中，PSNL导致Ca(V)2.2和Ca(V)2.3介导的Ca(2+)电流发生适应性变化，支持这些VDCCs在神经病变期间伤害感受中的作用。在Ca(V)2.3(-/-)小鼠中，PSNL诱导的Ca(V)1和Ca(V)2.2 Ca(2+)电流变化，与在缺乏Ca(V)2.3亚基时发生的替代适应性机制一致。
