Chen Xuanmao, Kalbacher Hubert, Gründer Stefan
Department of Physiology II, University of Würzburg, 97070 Würzburg, Germany.
J Gen Physiol. 2006 Mar;127(3):267-76. doi: 10.1085/jgp.200509409. Epub 2006 Feb 14.
Acid-sensing ion channels (ASICs) are Na(+) channels gated by extracellular H(+). Six ASIC subunits that are expressed in neurons have been characterized. The tarantula toxin psalmotoxin 1 has been reported to potently and specifically inhibit homomeric ASIC1a and has been useful to characterize ASICs in neurons. Recently we have shown that psalmotoxin 1 inhibits ASIC1a by increasing its apparent affinity for H(+). However, the mechanism by which PcTx1 increases the apparent H(+) affinity remained unclear. Here we show that PcTx1 also interacts with ASIC1b, a splice variant of ASIC1a. However, PcTx1 does not inhibit ASIC1b but promotes its opening; under slightly acidic conditions, PcTx1 behaves like an agonist for ASIC1b. Our results are most easily explained by binding of PcTx1 with different affinities to different states (closed, open, and desensitized) of the channel. For ASIC1b, PcTx1 binds most tightly to the open state, promoting opening, whereas for ASIC1a, it binds most tightly to the open and the desensitized state, promoting desensitization.
酸敏感离子通道（ASICs）是由细胞外H⁺门控的Na⁺通道。已鉴定出在神经元中表达的六种ASIC亚基。据报道，狼蛛毒素Psalmotoxin 1能有效且特异性地抑制同聚体ASIC1a，并且有助于在神经元中鉴定ASICs。最近我们发现，Psalmotoxin 1通过增加ASIC1a对H⁺的表观亲和力来抑制它。然而，PcTx1增加表观H⁺亲和力的机制仍不清楚。在这里我们表明，PcTx1也与ASIC1a的剪接变体ASIC1b相互作用。然而，PcTx1并不抑制ASIC1b，而是促进其开放；在微酸性条件下，PcTx1表现得像ASIC1b的激动剂。我们的结果最容易通过PcTx1以不同亲和力结合通道的不同状态（关闭、开放和脱敏）来解释。对于ASIC1b，PcTx1与开放状态结合最紧密，促进开放，而对于ASIC1a，它与开放和脱敏状态结合最紧密，促进脱敏。
