Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits.
Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits.
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DOI：
10.1177/1744806918765806
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发表时间：
2018-01
期刊：
影响因子：
3.3
通讯作者：
Smith PA
中科院分区：
文献类型：
--
作者：
Alles SR;Garcia E;Balasubramanyan S;Jones K;Tyson JR;Joy T;Snutch TP;Smith PA
周围神经慢性压迫损伤后，初级传入终末电压门控性钙通道α2δ-1辅助亚单位的积聚参与神经病理性疼痛的发生。α2δ-1在非洲爪蟾卵母细胞中的过表达增加了Cav1.2 L型通道的开放特性，并允许生理膜电位下的Ca 2+内流。因此，我们假设L型通道在神经病理性疼痛的慢性压迫损伤模型中浅背角神经递质释放中起作用。对坐骨神经慢性收缩损伤大鼠的II层神经元进行全细胞记录，结果显示L型钙通道阻滞剂尼群地平（2 μM）降低了自发兴奋性突触后电流的频率。尼群地平对假手术动物神经元自发兴奋性突触后电流频率几乎没有影响。为了确定α2δ-1是否参与上调Cav1.2 L型通道的功能，我们测试了α2δ-1配体加巴喷丁（100 µM）对表达Cav1.2/β4/α2δ-1通道的HEK 293 F细胞记录的电流的影响，发现峰值幅度显著降低，而对对照Cav1.2/β4/α2δ-3表达细胞无影响。在PC-12细胞，加巴喷丁也显着降低内源性二氢吡啶敏感的钙电流。在第二层，加巴喷丁减少自发兴奋性突触后电流频率的神经元受到慢性压迫性损伤，但不是在那些假手术动物。腹腔注射5 mg/kg尼群地平可增加慢性缩窄性损伤动物的缩爪阈值。我们认为，L-型通道表现出增加的贡献，在板II背角周围神经损伤后的突触传递。加巴喷丁通过α2δ-1对Cav1.2的影响可能有助于其抗异常性疼痛作用。
Following peripheral nerve chronic constriction injury, the accumulation of the α2δ–1 auxiliary subunit of voltage-gated Ca2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ–1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+ influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+ channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ–1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ–1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/β4/α2δ–1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/β4/α2δ–3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ–1 may contribute to its anti-allodynic action.
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DOI：
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发表时间：
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期刊：
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影响因子：
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