Yermolaieva Olena, Leonard A Soren, Schnizler Mikael K, Abboud Francois M, Welsh Michael J
Department of Internal Medicine and Physiology, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6752-7. doi: 10.1073/pnas.0308636100. Epub 2004 Apr 13.
Acid-sensing ion channel (ASIC) 1a subunit is expressed in synapses of central neurons where it contributes to synaptic plasticity. However, whether these channels can conduct Ca(2+) and thereby raise the cytosolic Ca(2+) concentration, Ca(2+), and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca(2+) entry and elevated Ca(2+) in wild-type, but not ASIC1(-/-), hippocampal neurons. Acid application also raised Ca(2+) and evoked Ca(2+) currents in heterologous cells expressing ASIC1a. Although ASIC2a is also expressed in central neurons, neither ASIC2a homomultimeric channels nor ASIC1a/2a heteromultimers showed H(+)-activated Ca(2+) elevation or Ca(2+) currents. Because extracellular acidosis accompanying cerebral ischemia contributes to neuronal injury, we tested the effect of acidosis on cell death measured as lactate dehydrogenase release. Eliminating ASIC1a from neurons or treating ASIC1a-expressing cells with the ASIC blocker amiloride attenuated acidosis-induced cell injury. These results indicate that ASIC1a provides a non-voltage-gated pathway for Ca(2+) to enter neurons. Thus, it may provide a target for modulation of Ca(2+).
酸敏感离子通道（ASIC）1a亚基在中枢神经元的突触中表达，它对突触可塑性有作用。然而，这些通道是否能够传导Ca(2+)，从而提高胞质Ca(2+)浓度Ca(2+)，并可能改变神经元生理学特性一直不确定。我们发现细胞外酸中毒会打开ASIC1a通道，这为野生型海马神经元而非ASIC1(-/-)海马神经元中的Ca(2+)内流和Ca(2+)升高提供了一条途径。施加酸也会提高表达ASIC1a的异源细胞中的Ca(2+)并诱发Ca(2+)电流。尽管ASIC2a也在中枢神经元中表达，但ASIC2a同多聚体通道和ASIC1a/2a异多聚体均未表现出H(+)激活的Ca(2+)升高或Ca(2+)电流。由于脑缺血伴随的细胞外酸中毒会导致神经元损伤，我们测试了酸中毒对以乳酸脱氢酶释放衡量的细胞死亡的影响。从神经元中去除ASIC1a或用ASIC阻滞剂阿米洛利处理表达ASIC1a的细胞可减轻酸中毒诱导的细胞损伤。这些结果表明ASIC1a为Ca(2+)进入神经元提供了一条非电压门控途径。因此，它可能为调节Ca(2+)提供一个靶点。
