Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions
Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions
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DOI：
10.1073/pnas.1120350109
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发表时间：
2012-08-07
影响因子：
11.1
通讯作者：
Deval, Emmanuel
中科院分区：
文献类型：
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作者：
Delaunay, Anne;Gasull, Xavier;Deval, Emmanuel
在啮齿动物感觉神经元中，酸敏感离子通道3（ASIC 3）最近已成为与组织酸中毒相关的非适应性疼痛的特别重要的传感器。然而，对人类ASIC 3通道知之甚少，其包括三种剪接变体，其C-末端结构域不同（hASIC 3a，hASIC 3b和hASIC 3c）。hASIC 3a转录物代表外周和中枢神经元组织（背根神经节[DRG]、脊髓和脑）中表达的主要mRNA，其中也检测到小比例的hASIC 3c转录物。我们发现，hASIC 3通道（hASIC 3a，hASIC 3b，或hASIC 3c）能够直接感知细胞外pH值的变化，不仅在酸化（pH值高达5.0），但也在碱化（pH值高达8.0），一个原始的和可诱导的属性还未知。如前所述，当外部pH降低时，hASIC 3显示出短暂的酸模式，其具有与经典ASIC电流相关的短暂激活。另一方面，外部pH增加激活持续的碱性模式，导致在静息pH下的组成型活性。这两种模式都受到APETx 2毒素（ASIC 3型通道抑制剂）的抑制。hASIC 3的碱性敏感性是通道的固有特性，其由细胞外环支持，并且涉及仅存在于人克隆中的两个丝氨酸（R68和R83）。因此，hASIC 3能够在两个方向上感测细胞外pH，并因此在pH 5.0和8.0之间动态地调整其活性，这是一种可能参与神经元膜电位的微调和在各种pH环境中神经元敏化的性质。
In rodent sensory neurons, acid-sensing ion channel 3 (ASIC3) has recently emerged as a particularly important sensor of nonadaptive pain associated with tissue acidosis. However, little is known about the human ASIC3 channel, which includes three splice variants differing in their C-terminal domain (hASIC3a, hASIC3b, and hASIC3c). hASIC3a transcripts represent the main mRNAs expressed in both peripheral and central neuronal tissues (dorsal root ganglia [DRG], spinal cord, and brain), where a small proportion of hASIC3c transcripts is also detected. We show that hASIC3 channels (hASIC3a, hASIC3b, or hASIC3c) are able to directly sense extracellular pH changes not only during acidification (up to pH 5.0), but also during alkalization (up to pH 8.0), an original and inducible property yet unknown. When the external pH decreases, hASIC3 display a transient acid mode with brief activation that is relevant to the classical ASIC currents, as previously described. On the other hand, an external pH increase activates a sustained alkaline mode leading to a constitutive activity at resting pH. Both modes are inhibited by the APETx2 toxin, an ASIC3-type channel inhibitor. The alkaline sensitivity of hASIC3 is an intrinsic property of the channel, which is supported by the extracellular loop and involves two arginines (R68 and R83) only present in the human clone. hASIC3 is thus able to sense the extracellular pH in both directions and therefore to dynamically adapt its activity between pH 5.0 and 8.0, a property likely to participate in the fine tuning of neuronal membrane potential and to neuron sensitization in various pH environments.