Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins
Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins
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DOI：
10.1073/pnas.0509863103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Takeshima, Hiroshi
中科院分区：
文献类型：
--
作者：
Moriguchi, Shigeki;Nishi, Miyuki;Takeshima, Hiroshi
由质膜和内质/肌浆网组成的连接膜复合物（JMCs）似乎是通道串扰的结构平台。亲结膜蛋白（Junctophilins, JPs）通过跨越肌浆网膜并与肌细胞的质膜结合，参与JMC的形成。在这篇文章中，我们报道了缺乏神经JP亚型的JP双敲除突变（JP- dko）小鼠表现出不规则的后肢反射和记忆受损。电生理实验表明，负责海马神经元后超极化的小电导Ca2+激活的K+通道的激活需要内质网Ca2+通过ryanodine受体释放，由NMDA受体介导的Ca2+内流触发。我们认为，在缺乏后超极化的JP-DKO神经元中，NMDA受体、ryanodine受体和小电导Ca2+激活的K+通道之间的功能通信由于JMC的解体而断开。此外，JP-DKO神经元显示Ca2+/钙调素依赖性蛋白激酶II的长期增强和过度激活受损。因此，jp似乎在神经兴奋性中起着至关重要的作用，这是可塑性和综合功能的基础。
Junctional membrane complexes (JMCs) composed of the plasma membrane and endoplasmic/sarcoplasmic reticulum seem to be a structural platform for channel crosstalk. Junctophilins (JPs) contribute to JMC formation by spanning the sarcoplasmic reticulum membrane and binding with the plasma membrane in muscle cells. In this article, we report that mutant JP double-knockout (JP-DKO) mice lacking neural JP subtypes exhibited an irregular hindlimb reflex and impaired memory. Electrophysiological experiments indicated that the activation of small-conductance Ca2+-activated K+ channels responsible for afterhyperpolarization in hippocampal neurons requires endoplasmic reticulum Ca2+ release through ryanodine receptors, triggered by NMDA receptor-mediated Ca2+ influx. We propose that in JP-DKO neurons lacking afterhyperpolarization, the functional communications between NMDA receptors, ryanodine receptors, and small-conductance Ca2+-activated K+ channels are disconnected because of JMC disassembly. Moreover, JP-DKO neurons showed an impaired long-term potentiation and hyperactivation of Ca2+/calmodulin-dependent protein kinase II. Therefore, JPs seem to have an essential role in neural excitability fundamental to plasticity and integrated functions.