Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO.
J Gen Physiol. 2021 Apr 5;153(4). doi: 10.1085/jgp.202012784.
Voltage-dependent sodium (Nav) current in adrenal chromaffin cells (CCs) is rapidly inactivating and tetrodotoxin (TTX)-sensitive. The fractional availability of CC Nav current has been implicated in regulation of action potential (AP) frequency and the occurrence of slow-wave burst firing. Here, through recordings of Nav current in rat CCs, primarily in adrenal medullary slices, we describe unique inactivation properties of CC Nav inactivation that help define AP firing rates in CCs. The key feature of CC Nav current is that recovery from inactivation, even following brief (5 ms) inactivation steps, exhibits two exponential components of similar amplitude. Various paired pulse protocols show that entry into the fast and slower recovery processes result from largely independent competing inactivation pathways, each of which occurs with similar onset times at depolarizing potentials. Over voltages from -120 to -80 mV, faster recovery varies from ∼3 to 30 ms, while slower recovery varies from ∼50 to 400 ms. With strong depolarization (above -10 mV), the relative entry into slow or fast recovery pathways is similar and independent of voltage. Trains of short depolarizations favor recovery from fast recovery pathways and result in cumulative increases in the slow recovery fraction. Dual-pathway fast inactivation, by promoting use-dependent accumulation in slow recovery pathways, dynamically regulates Nav availability. Consistent with this finding, repetitive AP clamp waveforms at 1-10 Hz frequencies reduce Nav availability 80-90%, depending on holding potential. These results indicate that there are two distinct pathways of fast inactivation, one leading to conventional fast recovery and the other to slower recovery, which together are well-suited to mediate use-dependent changes in Nav availability.
肾上腺嗜铬细胞（CCs）中的电压门控钠离子（Nav）电流迅速失活且对河豚毒素（TTX）敏感。CCs Nav 电流的分数可用性与动作电位（AP）频率的调节和慢波爆发发射的发生有关。在这里，我们通过记录大鼠 CCs 中的 Nav 电流，主要是在肾上腺髓质切片中，描述了 CC Nav 失活的独特失活特性，这些特性有助于确定 CCs 中的 AP 发射率。CC Nav 电流的关键特征是，即使在短暂（5ms）失活步骤之后，失活后的恢复也表现出相似幅度的两个指数分量。各种成对脉冲方案表明，进入快速和较慢恢复过程的原因是很大程度上独立的竞争性失活途径，每个途径在去极化电位下以相似的起始时间发生。在从-120 到-80mV 的超电压下，快速恢复的时间从约 3ms 到 30ms 不等，而较慢恢复的时间从约 50ms 到 400ms 不等。随着强去极化（超过-10mV），进入慢或快恢复途径的相对比例相似且与电压无关。短去极化的冲动有利于从快速恢复途径中恢复，导致慢恢复分数的累积增加。双途径快速失活通过促进慢恢复途径中的使用依赖性积累，动态调节 Nav 的可用性。与这一发现一致，在 1-10Hz 频率下的重复 AP 箝位波形根据保持电位使 Nav 可用性降低 80-90%。这些结果表明存在两种不同的快速失活途径，一种导致传统的快速恢复，另一种导致较慢的恢复，它们共同适合介导 Nav 可用性的使用依赖性变化。
