CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning.
CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning.
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DOI：
10.3389/fnmol.2013.00027
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发表时间：
2013
影响因子：
4.8
通讯作者：
Hodge JJ
中科院分区：
文献类型：
--
作者：
Gillespie JM;Hodge JJ
钙(Ca2+)/钙调素（CaM）依赖性激酶II （CaMKII）活性在学习和记忆中起着重要作用。CaMKII在记忆形成中的一个关键特征是其受自磷酸化调节的能力，自磷酸化在突触可塑性过程中开关其活性。突触支架蛋白CASK(钙（Ca2+)/钙调蛋白（CaM）相关丝氨酸激酶）对学习和记忆也很重要，因为CASK的突变会导致人类的智力残疾和神经缺陷。我们发现，在果蝇幼虫中，CASK与CaMKII相互作用以控制神经元生长和钙信号。此外，CASK的camk样结构域和L27结构域的缺失（CASK β null）或过度活跃的CaMKII （T287D）的表达对突触生长和Ca2+信号传导产生类似的影响。CASK过表达挽救了CaMKII过活性的影响，这与CASK和CaMKII在控制这些神经元过程的共同途径中起作用的概念一致。在CASK β零突变体中观察到的Ca2+信号的减少导致突触中囊泡运输的减少。此外，CASK突变体中Ca2+信号的减少与乙醚-à-go-go （EAG）钾（K+）通道定位到突触的增加有关。减少EAG使CASK突变体中Ca2+信号的减少恢复到野生型水平，表明CASK通过EAG调节Ca2+信号。CASK敲低降低了果蝇蘑菇体（果蝇的学习中心）的食欲联想学习和气味诱发的Ca2+反应。人CASK在果蝇中的表达挽救了CASK缺失对CaMKII活性状态的影响，提示人CASK也可能调节CaMKII的自磷酸化。
Calcium (Ca2+)/calmodulin (CaM)-dependent kinase II (CaMKII) activity plays a fundamental role in learning and memory. A key feature of CaMKII in memory formation is its ability to be regulated by autophosphorylation, which switches its activity on and off during synaptic plasticity. The synaptic scaffolding protein CASK (calcium (Ca2+)/calmodulin (CaM) associated serine kinase) is also important for learning and memory, as mutations in CASK result in intellectual disability and neurological defects in humans. We show that in Drosophila larvae, CASK interacts with CaMKII to control neuronal growth and calcium signaling. Furthermore, deletion of the CaMK-like and L27 domains of CASK (CASK β null) or expression of overactive CaMKII (T287D) produced similar effects on synaptic growth and Ca2+ signaling. CASK overexpression rescues the effects of CaMKII overactivity, consistent with the notion that CASK and CaMKII act in a common pathway that controls these neuronal processes. The reduction in Ca2+ signaling observed in the CASK β null mutant caused a decrease in vesicle trafficking at synapses. In addition, the decrease in Ca2+ signaling in CASK mutants was associated with an increase in Ether-à-go-go (EAG) potassium (K+) channel localization to synapses. Reducing EAG restored the decrease in Ca2+ signaling observed in CASK mutants to the level of wildtype, suggesting that CASK regulates Ca2+ signaling via EAG. CASK knockdown reduced both appetitive associative learning and odor evoked Ca2+ responses in Drosophila mushroom bodies, which are the learning centers of Drosophila. Expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation.
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