Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with NaV1.9.
Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with NaV1.9.
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DOI：
10.1097/j.pain.0000000000002421
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发表时间：
2022-04-01
期刊：
影响因子：
7.4
通讯作者：
Liu JY
中科院分区：
文献类型：
--
作者：
Ma T;Li L;Chen R;Yang L;Sun H;Du S;Xu X;Cao Z;Zhang X;Zhang L;Shi X;Liu JY
补充数字内容在文本中可用。蛋白精氨酸甲基转移酶7通过与NaV1.9相互作用并使其甲基化来调节NaV1.9电流和神经元兴奋性，而蛋白精氨酸甲基转移酶7抑制剂（DS-437）抑制Scn 11 a A796 G/A796 G小鼠背根神经节神经元的动作电位频率。由SCN 11 A编码的人NaV1.9（hNaV1.9）优先在伤害感受器中表达，其突变与疼痛障碍有关。NaV1.9可能是一个有前途的止痛药物靶点。然而，NaV1.9活性的调节仍然难以捉摸。在这里，我们确定了一个新的候选人NaV1.9相互作用的合作伙伴，蛋白质精氨酸甲基转移酶7（PRMT 7）。全细胞电压钳记录显示，在Scn 11 a −/−小鼠背根神经节（DRG）神经元中共电穿孔人SCN 11 A和PRMT 7增加了hNaV1.9电流密度。相比之下，PRMT 7抑制剂（DS-437）降低了Scn 11 a +/+小鼠中的mNaV1.9电流。使用报告分子CD 4，我们观察到在PRMT 7过表达的HKE 293 T细胞的细胞表面上hLoop 1的分布增加。此外，我们发现PRMT 7主要结合hNaV1.9（hLoop 1）的第一胞内环内的残基563至566，并在精氨酸残基519处甲基化hLoop 1。此外，PRMT 7的过表达增加了Scn 11 a +/+小鼠而不是Scn 11 a −/−小鼠DRG神经元中激发的动作电位数量。然而，DS-437显著抑制了Scn 11 a A796 G/A796 G小鼠DRG神经元的动作电位频率，并减轻了疼痛超敏反应。总之，我们的观察结果表明，PRMT 7通过调节NaV1.9电流来调节神经元兴奋性，这可能为疼痛治疗提供一种潜在的方法。
Supplemental Digital Content is Available in the Text. Protein arginine methyltransferase 7 modulates NaV1.9 currents and neuronal excitability by interacting with and methylating NaV1.9, whereas protein arginine methyltransferase 7 inhibitor (DS-437) inhibits the action potential frequency of dorsal root ganglion neurons in Scn11a A796G/A796G mice. Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage-clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglion (DRG) neurons of Scn11a −/− mice increased the hNaV1.9 current density. By contrast, a PRMT7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a +/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563 to 566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of PRMT7 increased the number of action potential fired in DRG neurons of Scn11a +/+ mice but not Scn11a −/− mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11a A796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment.
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影响因子：
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作者：
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通讯作者：
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影响因子：
16.6
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