Alternative splicing and interaction with di- and polyvalent cations control the dynamic range of acid-sensing ion channel 1 (ASIC1)
Alternative splicing and interaction with di- and polyvalent cations control the dynamic range of acid-sensing ion channel 1 (ASIC1)
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DOI：
10.1074/jbc.m205877200
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发表时间：
2002-11-01
影响因子：
4.8
通讯作者：
Gründer, S
中科院分区：
文献类型：
--
作者：
Babini, E;Paukert, M;Gründer, S
同质酸敏感离子通道 1 (ASIC1) 可在生理 pH 范围内被细胞外 H+ 激活，因此可能有助于神经传递和外周疼痛感知。 ASIC1a和ASIC1b是ASIC1基因的选择性剪接产物。在这里，我们表明，当暴露于稍微降低的 pH 值时，两种剪接变体都表现出稳态失活，从而限制了它们的操作范围。与 ASIC1a 相比，ASIC1b 的稳态失活和 pH 激活分别向酸性值偏移 0.25 和 0.7 个 pH 单位，从而扩展了 ASIC1 的动态范围。失活和激活的转变密切相关；胞外域中只有两个氨基酸通过选择性剪接进行交换，控制着这两种特性。此外，我们发现细胞外二价阳离子（如 Ca2+ 和 Mg2+）以及多价阳离子精胺将 ASIC1a 和 ASIC1b 的稳态失活转变为酸性值。这导致通道响应增强，并且归因于静息状态的稳定。我们的结果表明，ASIC1b 是轻微酸中毒期间瞬态 H+ 信号的有效传感器，并且除了选择性剪接之外，与二价和多价阳离子的相互作用扩展了 ASIC H+ 传感器的动态范围。
Homomeric acid-sensing ion channel 1 (ASIC1) can be activated by extracellular H+ in the physiological pH range and may, therefore, contribute to neurotransmission and peripheral pain perception. ASIC1a and ASIC1b are alternative splice products of the ASIC1 gene. Here we show that both splice variants show steady-state inactivation when exposed to slightly decreased pH, limiting their operational range. Compared with ASIC1a, steady-state inactivation and pH activation of ASIC1b are shifted to more acidic values by 0.25 and 0.7 pH units, respectively, extending the dynamic range of ASIC1. Shifts of inactivation and activation are intimately linked; only two amino acids in the ectodomain, which are exchanged by alternative splicing, control both properties. Moreover, we show that extracellular, divalent cations like Ca2+ and Mg2+ as well as the polyvalent cation spermine shift the steady-state inactivation of ASIC1a and ASIC1b to more acidic values. This leads to a potentiation of the channel response and is due to a stabilization of the resting state. Our results indicate that ASIC1b is an effective sensor of transient H+ signals during slight acidosis and that, in addition to alternative splicing, interaction with di- and polyvalent cations extends the dynamic range of ASIC H+ sensors.