Current understanding of iberiotoxin-resistant BK channels in the nervous system.
Current understanding of iberiotoxin-resistant BK channels in the nervous system.
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DOI：
10.3389/fphys.2014.00382
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发表时间：
2014
影响因子：
4
通讯作者：
Brenner R
中科院分区：
文献类型：
--
作者：
Wang B;Jaffe DB;Brenner R
虽然大多数大电导、钙和电压激活的钾通道（BK 或 Maxi-K 型）会被蝎毒伊贝里奥毒素阻断，但所谓的“II 型”亚型具有毒素抗性。这一特性是由 BK 辅助 β 亚基家族成员之一（富含神经元的 β4 亚基）的通道组装来独特介导的。本综述将重点关注目前对伊比利亚毒素抗性、含 β4 BK 通道特性及其在中枢神经系统中功能的理解。研究表明，β4 通过将电压传感器激活转移到更负的电压范围来显着促进 BK 通道开放，但也会将激活减慢到理论上排除 BK 形成动作电位 (AP) 的能力的时间尺度。此外，β4 膜运输通过内质滞留信号和棕榈酰化进行调节。最近的挑战是利用神经元计算模型和神经生理学方法来了解伊比利亚毒素抗性 BK 亚型的功能作用。利用伊比利亚毒素抗性作为这些通道的足迹，已在齿状回颗粒神经元和小脑的浦肯野神经元中鉴定出它们。在这些神经元中，这些通道的作用在很大程度上与慢门控通道一致，慢门控通道通过尖峰间电导降低兴奋性，例如在浦肯野神经元中，或者通过替换快速门控 BK 通道，否则促进高频 AP 放电，例如在齿状回神经元中。在齿状回的突触前苔藓纤维末梢和垂体后叶末梢中也观察到它们。最近的研究表明，β4 亚基也可能在一些缺乏伊比利亚毒素抗性 BK 通道的神经元中表达，例如 CA3 海马神经元。正在进行的使用 BK/β4 和 β4 敲除小鼠的新型特异性阻断剂和激动剂的研究将继续推动该领域进一步了解这些通道的功能。
While most large-conductance, calcium-, and voltage-activated potassium channels (BK or Maxi-K type) are blocked by the scorpion venom iberiotoxin, the so-called “type II” subtype has the property of toxin resistance. This property is uniquely mediated by channel assembly with one member of the BK accessory β subunit family, the neuron-enriched β4 subunit. This review will focus on current understanding of iberiotoxin-resistant, β4-containing BK channel properties and their function in the CNS. Studies have shown that β4 dramatically promotes BK channel opening by shifting voltage sensor activation to more negative voltage ranges, but also slows activation to timescales that theoretically preclude BK ability to shape action potentials (APs). In addition, β4 membrane trafficking is regulated through an endoplasmic retention signal and palmitoylation. More recently, the challenge has been to understand the functional role of the iberiotoxin-resistant BK subtype utilizing computational modeling of neurons and neurophysiological approaches. Utilizing iberiotoxin-resistance as a footprint for these channels, they have been identified in dentate gyrus granule neurons and in purkinje neurons of the cerebellum. In these neurons, the role of these channels is largely consistent with slow-gated channels that reduce excitability either through an interspike conductance, such as in purkinje neurons, or by replacing fast-gating BK channels that otherwise facilitate high frequency AP firing, such as in dentate gyrus neurons. They are also observed in presynaptic mossy fiber terminals of the dentate gyrus and posterior pituitary terminals. More recent studies suggest that β4 subunits may also be expressed in some neurons lacking iberiotoxin-resistant BK channels, such as in CA3 hippocampus neurons. Ongoing research using novel, specific blockers and agonists of BK/β4, and β4 knockout mice, will continue to move the field forward in understanding the function of these channels.
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DOI：
10.1085/jgp.109.5.647
发表时间：
1997-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1216953109
发表时间：
2012-11-13
影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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