We show here that hyperpolarization-activated current (I_h) unexpectedly acts to inhibit the activity of dorsal root ganglion (DRG) neurons expressing WT Nav1.7, the largest inward current and primary driver of DRG neuronal firing, and hyperexcitable DRG neurons expressing a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain. In this study we created a kinetic model of I_h and used it, in combination with dynamic-clamp, to study I_h function in DRG neurons. We show, for the first time, that I_h increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by I_h. Our results show that I_h, due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that I_h reverses the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. In the aggregate, our results show that I_h unexpectedly has strikingly different effects in DRG neurons as compared to previously- and well-studied cardiac cells. Within DRG neurons where Nav1.7 is present, I_h reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of I_h direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of I_h limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM.

我们在此表明​​，超极化激活电流（ I _h ）出乎意料地抑制了表达 WT Nav1.7 的背根神经节（DRG）神经元的活动，WT Nav1.7 是 DRG 神经元放电的最大内向电流和主要驱动因素，以及表达 a 的过度兴奋的 DRG 神经元。功能获得性 Nav1.7 突变会导致遗传性红斑性肢痛症 (IEM)，这是一种人类神经性疼痛的遗传模型。在本研究中，我们创建了I _h动力学模型，并将其与动态钳结合使用来研究 DRG 神经元中的I _h功能。我们首次证明， I _h会增加流变碱并降低小 DRG 神经元的放电概率，并证明I _h会降低阈下振荡的幅度。我们的结果表明，由于门控缓慢， I _h在动作电位 (AP) 期间不会失活，并且具有显着的阻尼作用，从去极化反转为超极化，接近 AP 生成的阈值。此外，我们发现I _h可以逆转 DRG 神经元的过度兴奋，这些神经元表达功能获得性 Nav1.7 突变，从而导致 IEM。总的来说，我们的结果表明，与之前经过充分研究的心肌细胞相比， I _h对 DRG 神经元具有意想不到的显着不同的影响。在存在 Nav1.7 的 DRG 神经元内，由于 Nav1 的增强， I _h减少了去极化钠电流流入。7 通道快速失活，并通过将I _h方向从去极化反转到接近 AP 生成阈值的超极化来产生额外的阻尼作用。 I _h的这些作用限制了表达 WT Nav1.7 的 DRG 神经元的放电，并逆转了表达功能获得性 Nav1.7 突变（导致 IEM）的 DRG 神经元的过度兴奋。