Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation
Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation
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DOI：
10.1113/jphysiol.2008.160861
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发表时间：
2008-11-01
影响因子：
5.5
通讯作者：
Kaczmarek, Leonard K.
中科院分区：
文献类型：
--
作者：
Brown, Maile R.;Kronengold, Jack;Kaczmarek, Leonard K.
在不同类型的神经元中，Na+激活的K+ (K-Na)电流的激活率和单一性质有很大差异。一类K-Na通道由Slack基因编码。我们现在已经确定，可选择的RNA剪接产生至少五种不同的Slack转录本，这些转录本产生的Slack通道在其预测的细胞质氨基末端和动力学特性上有所不同。其中两个通道被称为Slack-A通道，包含一个氨基末端结构域，与Slick基因编码的另一类K-Na通道非常相似。Slack- a通道和先前描述的Slack亚型（现在称为Slack- b）的神经元表达是由独立启动子驱动的。Slack-A mrna在脑干和嗅球中富集，并在四个不同的大脑区域中检测到显著水平。当在CHO细胞中表达时，slacka通道在去极化后迅速激活，并且在非洲爪蟾卵母细胞的单通道记录中，其特征是多个亚电导状态，只有短暂的瞬间开放到完全开放状态。相比之下，Slack-B通道在数百毫秒内缓慢激活，其打开到完全打开状态的时间大约是Slack-A通道的6倍。在数值模拟中，向外电流由类似于懒散a的电导主导的神经元，可以非常迅速地适应在大范围的刺激强度上重复或维持的刺激。相比之下，在持续刺激期间，松弛- b电流促进有节奏的放电，并允许适应率随刺激强度而变化。使用一种能够识别Slack所有氨基末端同型异构体的抗体，Slack的免疫反应性存在于没有Slack- b特异性染色的位置，包括嗅球肾小球和海马神经元的树突，这表明具有替代氨基末端的Slack通道（如Slack- a通道）存在于这些位置。我们的数据表明，Slack基因的不同启动子对神经元的特性有不同的调节作用。
The rates of activation and unitary properties of Na+-activated K+ (K-Na) currents have been found to vary substantially in different types of neurones. One class of K-Na channels is encoded by the Slack gene. We have now determined that alternative RNA splicing gives rise to at least five different transcripts for Slack, which produce Slack channels that differ in their predicted cytoplasmic amino-termini and in their kinetic properties. Two of these, termed Slack-A channels, contain an amino-terminus domain closely resembling that of another class of K-Na channels encoded by the Slick gene. Neuronal expression of Slack-A channels and of the previously described Slack isoform, now called Slack-B, are driven by independent promoters. Slack-A mRNAs were enriched in the brainstem and olfactory bulb and detected at significant levels in four different brain regions. When expressed in CHO cells, Slack-A channels activate rapidly upon depolarization and, in single channel recordings in Xenopus oocytes, are characterized by multiple subconductance states with only brief transient openings to the fully open state. In contrast, Slack-B channels activate slowly over hundreds of milliseconds, with openings to the fully open state that are similar to 6-fold longer than those for Slack-A channels. In numerical simulations, neurones in which outward currents are dominated by a Slack-A-like conductance adapt very rapidly to repeated or maintained stimulation over a wide range of stimulus strengths. In contrast, Slack-B currents promote rhythmic firing during maintained stimulation, and allow adaptation rate to vary with stimulus strength. Using an antibody that recognizes all amino-termini isoforms of Slack, Slack immunoreactivity is present at locations that have no Slack-B-specific staining, including olfactory bulb glomeruli and the dendrites of hippocampal neurones, suggesting that Slack channels with alternate amino-termini such as Slack-A channels are present at these locations. Our data suggest that alternative promoters of the Slack gene differentially modulate the properties of neurones.