Catalytically Dead αCaMKII K42M Mutant Acts as a Dominant Negative in the Control of Synaptic Strength
Catalytically Dead αCaMKII K42M Mutant Acts as a Dominant Negative in the Control of Synaptic Strength
复制标题
催化死亡 αCaMKII K42M 突变体在突触强度的控制中充当显性阴性蛋白
作者：
A. Kabakov;J. Lisman
在兴奋性突触的长时程增强（LTP）过程中，Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）被通过NMDA受体的Ca 2+内流激活，NMDA受体通过在突触处插入额外的含GluR 1的受体和通过增加AMPA通道电导以及通过刺激结构变化来增强AMPA受体电流。CaMKII也参与LTP的维持，并有助于维持可卡因或安非他明的行为敏感性。最近的研究表明，接触安非他明后，催化死亡的αCaMKII K42 M突变体的瞬时表达持续逆转成瘾的行为效应。一个建议的解释是，这种突变体作为一个显性负控制突触强度，但这种解释还没有经过生理学测试。本研究在体外培养的大鼠海马脑片上观察了单个CA 1区锥体神经元表达的α CaMK Ⅱ K42 M突变体对基础兴奋性神经传递的影响。突变体导致基础CA 3-CA 1传递减少近50%，而野生型α CaMK II的过表达没有影响。这一结果与显性否定假说相一致，但存在复杂性。我们发现，当TTX转染后切片中的活性被抑制或NMDA受体被APV阻断时，基础传输的减少并没有发生。因此，显性负效应需要神经活动来表达。
During long-term potentiation (LTP) of excitatory synapses, Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by Ca2+ influx through NMDA receptors that potentiate AMPA receptor currents by insertion of additional GluR1-containing receptors at the synapse and by increasing AMPA channel conductance, as well as by stimulating structural changes. CaMKII is also involved in the maintenance of LTP and contributes to maintenance of behavioral sensitization by cocaine or amphetamine. Recent studies show that transient expression of catalytically dead αCaMKII K42M mutant after exposure to amphetamine persistently reverses the behavioral effects of the addiction. A suggested interpretation is that this mutant acts as a dominant negative in the control of synaptic strength, but this interpretation has not been physiologically tested. Here we investigate the effect of αCaMKII K42M mutant expressed in single CA1 pyramidal neurons on basal excitatory neurotransmission in cultured rat hippocampal organotypic slices. The mutant caused nearly 50% reduction in the basal CA3–CA1 transmission, while overexpression of the wild-type αCaMKII had no effect. This result is consistent with the dominant negative hypothesis, but there are complexities. We found that the decrease in basal transmission did not occur when activity in the slices was suppressed after transfection by TTX or when NMDA receptors were blocked by APV. Thus, the dominant negative effect requires neural activity for its expression.
DOI：
10.1073/pnas.96.6.3269
发表时间：
1999-03-16
影响因子：
11.1
作者：
Derkach, V;Barria, A;Soderling, TR
通讯作者：
Soderling, TR
影响因子：
56.9
作者：
MALINOW, R;SCHULMAN, H;TSIEN, RW
通讯作者：
TSIEN, RW
影响因子：
56.9
作者：
Giese, KP;Fedorov, NB;Silva, AJ
通讯作者：
Silva, AJ