Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors
Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors
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DOI：
10.1073/pnas.96.6.3269
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Soderling, TR
中科院分区：
文献类型：
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作者：
Derkach, V;Barria, A;Soderling, TR
中枢神经元能突触响应于突触输入的强度而改变其强度的能力（例如，在长时程增强（LTP）中发生）被认为为记忆形成和学习提供了细胞基础。海马CA 1区的LTP需要激活Ca 2 +/钙调蛋白激酶II（CaM-KII），其磷酸化α-氨基-3-羟基-5-甲基-4-异恶唑丙酸谷氨酸受体（AMPA-R）的GluR 1亚单位中的Ser-831，并且这种激活/磷酸化被认为是LTP中的突触后机制。在这项研究中，我们已经确定了CaM-KII增强AMPA-Rs的分子机制。在HEK-293细胞中共表达激活的CaM-KII与GluR 1并不影响受体的谷氨酸亲和力、脱敏和恢复的动力学、通道整流、开放概率或门控。单通道记录确定了GluR 1的多个电导状态，并且与CaM-KII或Ser-831突变为Asp的共表达增加了较高电导状态的贡献。这些结果表明，CaM-KII可以通过增加现有功能性AR的单通道电导，IPA-Rs或通过招募新的高电导状态AMPA-Rs来介导突触的可塑性。
The ability of central glutamatergic synapses to change their strength in response to the intensity of synaptic input, which occurs, for example, in long-term potentiation (LTP), is thought to provide a cellular basis for memory formation and learning. LTP in the CA1 field of the hippocampus requires activation of Ca2+/calmodulin-kinase II (CaM-KII), which phosphorylates Ser-831 in the GluR1 sub unit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor (AMPA-R), and this activation/phosphorylation is thought to be a postsynaptic mechanism in LTP, In this study, we have identified a molecular mechanism by which CaM-KII potentiates AMPA-Rs. Coexpression in HEK-293 cells of activated CaM-KII with GluR1 did not affect the glutamate affinity of the receptor, the kinetics of desensitization and recovery, channel rectification, open probability, or gating, Single-channel recordings identified multiple conductance states for GluR1, and coexpression with CaM-KII or a mutation of Ser-831 to Asp increased the contribution of the higher conductance states. These results indicate that CaM-KII can mediate plasticity at glutamatergic synapses by increasing single-channel conductance of existing functional AR;IPA-Rs or by recruiting new high-conductance-state AMPA-Rs.