...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Palmitoylation Gates Phosphorylation-dependent Regulation Of Bk Potassium Channels
【24h】

Palmitoylation Gates Phosphorylation-dependent Regulation Of Bk Potassium Channels

机译：Palmitoylation门磷酸化依赖调节的钾钾通道。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Large conductance calcium- and voltage-gated potassium (BK) channels are important regulators of physiological homeostasis and their function is potently modulated by protein kinase A (PKA) phosphorylation. PKA regulates the channel through phosphory-lation of residues within the intracellular C terminus of the pore-forming α-subunits. However, the molecular mechanism(s) by which phosphorylation of the α-subunit effects changes in channel activity are unknown. Inhibition of BK channels by PKA depends on phosphorylation of only a single α-subunit in the channel tetramer containing an alternatively spliced insert (STREX) suggesting that phosphorylation results in major conformational rearrangements of the C terminus. Here, we define the mechanism of PKA inhibition of BK channels and demonstrate that this regulation is conditional on the palmitoylation status of the channel. We show that the cytosolic C terminus of the STREX BK channel uniquely interacts with the plasma membrane via palmitoylation of evolutionarily conserved cysteine residues in the STREX insert. PKA phosphorylation of the serine residue immediately upstream of the conserved palmitoylated cysteine residues within STREX dissociates the C terminus from the plasma membrane, inhibiting STREX channel activity. Abolition of STREX palmitoylation by site-directed mu-tagenesis or pharmacological inhibition of palmitoyl transferases prevents PKA-mediated inhibition of BK channels. Thus, palmitoylation gates BK channel regulation by PKA phosphorylation. Palmitoylation and phosphorylation are both dynamically regulated; thus, cross-talk between these 2 major posttranslational signaling cascades provides a mechanism for conditional regulation of BK channels. Interplay of these distinct signaling cascades has important implications for the dynamic regulation of BK channels and physiological homeostasis.
机译：大电导的钙和电压门控钾（BK）通道是生理稳态的重要调节剂，其功能受蛋白激酶A（PKA）磷酸化的调节。 PKA通过形成孔的α-亚基的细胞内C端残基的磷酸化来调节通道。然而，α-亚基的磷酸化作用改变通道活性的分子机制尚不清楚。 PKA对BK通道的抑制作用仅取决于通道四聚体中含有一个交替剪接的插入片段（STREX）的单个α亚基的磷酸化，这表明磷酸化会导致C末端的主要构象重排。在这里，我们定义了PKA抑制BK通道的机制，并证明该调节取决于通道的棕榈酰化状态。我们显示，STREX BK通道的胞质C末端通过STREX插入物中进化上保守的半胱氨酸残基的棕榈酰化与质膜发生唯一相互作用。 STREX内保守的棕榈酰化半胱氨酸残基上游的丝氨酸残基的PKA磷酸化可将C末端与质膜解离，从而抑制STREX通道活性。通过定点诱变或药理学抑制棕榈酰转移酶消除STREX棕榈酰化可防止PKA介导的BK通道抑制。因此，棕榈酰化通过PKA磷酸化门控BK通道调节。棕榈酰化和磷酸化都是动态调节的。因此，这两个主要的翻译后信号转导级联之间的串扰为BK通道的条件调节提供了一种机制。这些不同的信号级联反应的相互作用对BK通道的动态调节和生理稳态具有重要意义。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号