Alijevic Omar, Peng Zhong, Kellenberger Stephan
Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
Front Cell Neurosci. 2021 Oct 15;15:732869. doi: 10.3389/fncel.2021.732869. eCollection 2021.
Acid-sensing ion channels (ASICs) are activated by extracellular acidification. Because ASIC currents are transient, these channels appear to be ideal sensors for detecting the onset of rapid pH changes. ASICs are involved in neuronal death after ischemic stroke, and in the sensation of inflammatory pain. Ischemia and inflammation are associated with a slowly developing, long-lasting acidification. Recent studies indicate however that ASICs are unable to induce an electrical signaling activity under standard experimental conditions if pH changes are slow. In situations associated with slow and sustained pH drops such as high neuronal signaling activity and ischemia, the extracellular K concentration increases, and the Ca concentration decreases. We hypothesized that the concomitant changes in H, K, and Ca concentrations may allow a long-lasting ASIC-dependent induction of action potential (AP) signaling. We show that for acidification from pH7.4 to pH7.0 or 6.8 on cultured cortical neurons, the number of action potentials and the firing time increased strongly if the acidification was accompanied by a change to higher K and lower Ca concentrations. Under these conditions, APs were also induced in neurons from ASIC1a mice, in which a pH of ≤ 5.0 would be required to activate ASICs, indicating that ASIC activation was not required for the AP induction. Comparison between neurons of different ASIC genotypes indicated that the ASICs modulate the AP induction under such changed ionic conditions. Voltage-clamp measurements of the Na and K currents in cultured cortical neurons showed that the lowering of the pH inhibited Na and K currents. In contrast, the lowering of the Ca together with the increase in the K concentration led to a hyperpolarizing shift of the activation voltage dependence of voltage-gated Na channels. We conclude that the ionic changes observed during high neuronal activity mediate a sustained AP induction caused by the potentiation of Na currents, a membrane depolarization due to the changed K reversal potential, the activation of ASICs, and possibly effects on other ion channels. Our study describes therefore conditions under which slow pH changes induce neuronal signaling by a mechanism involving ASICs.
酸敏感离子通道（ASICs）可被细胞外酸化激活。由于ASIC电流是瞬态的，这些通道似乎是检测快速pH变化起始的理想传感器。ASICs参与缺血性中风后的神经元死亡以及炎性疼痛的感觉。缺血和炎症与缓慢发展的、持久的酸化有关。然而，最近的研究表明，如果pH变化缓慢，ASICs在标准实验条件下无法诱导电信号活动。在与缓慢且持续的pH下降相关的情况下，如高神经元信号活动和缺血，细胞外钾浓度升高，钙浓度降低。我们推测，H、K和Ca浓度的伴随变化可能允许由ASICs介导的持久动作电位（AP）信号诱导。我们发现，对于培养的皮质神经元从pH7.4酸化至pH7.0或6.8，如果酸化伴随着钾浓度升高和钙浓度降低，动作电位的数量和发放时间会显著增加。在这些条件下，ASIC1a小鼠的神经元也能诱导产生动作电位，而在该小鼠中，激活ASICs需要pH≤5.0，这表明AP诱导并不需要ASIC激活。不同ASIC基因型神经元之间的比较表明，在这种离子条件改变的情况下，ASICs调节AP诱导。对培养的皮质神经元中钠和钾电流的电压钳测量表明，pH降低会抑制钠和钾电流。相反，钙浓度降低与钾浓度升高会导致电压门控钠通道激活电压依赖性的超极化偏移。我们得出结论，在高神经元活动期间观察到的离子变化介导了由钠电流增强、由于钾反转电位改变导致的膜去极化、ASICs激活以及可能对其他离子通道的影响所引起的持续AP诱导。因此，我们的研究描述了缓慢pH变化通过涉及ASICs的机制诱导神经元信号传导的条件。
