Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons
Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons
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DOI：
10.3389/fncel.2020.00041
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发表时间：
2020-02-28
影响因子：
5.3
通讯作者：
Kellenberger, Stephan
中科院分区：
文献类型：
--
作者：
Alijevic, Omar;Bignucolo, Olivier;Kellenberger, Stephan
酸敏感离子通道（ASIC）是H+激活的神经元Na+通道。它们参与恐惧行为、学习、缺血性中风后的神经变性和疼痛感觉。到目前为止，ASIC活化仅在快速pH变化的情况下进行了研究，尽管与ASIC的许多作用相关的pH变化是缓慢的。目前尚不清楚缓慢的pH变化是否可以打开ASIC。在这里，我们研究了缓慢的pH变化在多大程度上可以激活ASIC 1a通道并诱导动作电位信号。为此，在转染的中国仓鼠卵巢细胞中测量ASIC 1a电流幅度和电荷转运，以及在培养的皮层神经元中测量ASIC介导的动作电位信号，以响应从pH 7.4至pH 6.6或6.0的1-40 s持续时间的限定pH斜坡。ASIC 1a电流的动力学模型被开发并整合到Hodgkin-Huxley动作电位模型中。有趣的是，虽然ASIC 1a电流幅度随着pH值的下降而下降，但皮层神经元中的中间酸化比快速酸化时的动作电位放电更高。事实上，在许多实验中，快速pH变化（10秒）并不产生动作电位。计算机模拟证实了这些观察结果。我们在这里首次描述了ASIC响应定义的缓慢pH变化的功能。我们的研究表明，ASIC 1a电流和ASIC 1a电流诱导的神经元活动强烈依赖于pH变化的速度。重要的是，pH值变化需要>10秒才能完成，ASIC 1a激活效率低下。因此，目前未知的调节机制可能允许ASIC在缺血和炎症等情况下活动。
Acid-sensing ion channels (ASICs) are H+-activated neuronal Na+ channels. They are involved in fear behavior, learning, neurodegeneration after ischemic stroke and in pain sensation. ASIC activation has so far been studied only with fast pH changes, although the pH changes associated with many roles of ASICs are slow. It is currently not known whether slow pH changes can open ASICs at all. Here, we investigated to which extent slow pH changes can activate ASIC1a channels and induce action potential signaling. To this end, ASIC1a current amplitudes and charge transport in transfected Chinese hamster ovary cells, and ASIC-mediated action potential signaling in cultured cortical neurons were measured in response to defined pH ramps of 1-40 s duration from pH 7.4 to pH 6.6 or 6.0. A kinetic model of the ASIC1a current was developed and integrated into the Hodgkin-Huxley action potential model. Interestingly, whereas the ASIC1a current amplitude decreased with slower pH ramps, action potential firing was higher upon intermediate than fast acidification in cortical neurons. Indeed, fast pH changes (10 s) did in many experiments not generate action potentials. Computer simulations corroborated these observations. We provide here the first description of ASIC function in response to defined slow pH changes. Our study shows that ASIC1a currents, and neuronal activity induced by ASIC1a currents, strongly depend on the speed of pH changes. Importantly, with pH changes that take >10 s to complete, ASIC1a activation is inefficient. Therefore, it is likely that currently unknown modulatory mechanisms allow ASIC activity in situations such as ischemia and inflammation.