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调控长时程增强（LTP）与长时程抑制（LTD）抉择的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）全酶机制。

CaMKII holoenzyme mechanisms that govern the LTP versus LTD decision.

作者信息

Cook Sarah G, Buonarati Olivia R, Coultrap Steven J, Bayer K Ulrich

机构信息

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

出版信息

Sci Adv. 2021 Apr 14;7(16). doi: 10.1126/sciadv.abe2300. Print 2021 Apr.

DOI:10.1126/sciadv.abe2300
PMID:33853773
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8046365/
Abstract

Higher brain functions are thought to require synaptic frequency decoding that can lead to long-term potentiation (LTP) or depression (LTD). We show that the LTP versus LTD decision is determined by complex cross-regulation of T286 and T305/306 autophosphorylation within the 12meric CaMKII holoenzyme, which enabled molecular computation of stimulus frequency, amplitude, and duration. Both LTP and LTD require T286 phosphorylation, but T305/306 phosphorylation selectively promoted LTD. In response to excitatory LTP versus LTD stimuli, the differential T305/306 phosphorylation directed CaMKII movement to either excitatory or inhibitory synapses, thereby coordinating plasticity at both synapse types. Fast T305/306 phosphorylation required prior T286 phosphorylation and then curbed CaMKII activity by two mechanisms: (i) a cis-subunit reaction reduced both Ca stimulation and autonomous activity and (ii) a trans-subunit reaction enabled complete activity shutdown and feed-forward inhibition of further T286 phosphorylation. These are fundamental additions to the long-studied CaMKII regulation and function in neuronal plasticity.

摘要

高级脑功能被认为需要突触频率解码，而这可能导致长时程增强（LTP）或长时程抑制（LTD）。我们发现，LTP与LTD的决定是由12聚体CaMKII全酶内T286和T305/306自身磷酸化的复杂交叉调节所决定的，这使得能够对刺激频率、幅度和持续时间进行分子计算。LTP和LTD都需要T286磷酸化，但T305/306磷酸化选择性地促进LTD。响应兴奋性LTP与LTD刺激，差异性的T305/306磷酸化将CaMKII的运动导向兴奋性或抑制性突触，从而协调两种突触类型的可塑性。快速的T305/306磷酸化需要先有T286磷酸化，然后通过两种机制抑制CaMKII活性：（i）顺式亚基反应降低了钙刺激和自主活性，（ii）反式亚基反应导致完全的活性关闭和对进一步T286磷酸化的前馈抑制。这些是对长期研究的CaMKII在神经元可塑性中的调节和功能的重要补充。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/7fc0f876a38b/abe2300-F9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/7fc0f876a38b/abe2300-F9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/18b4a4666439/abe2300-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/a5bd0b963035/abe2300-F2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/1ff3b6ae33a4/abe2300-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/a3ceb733038b/abe2300-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/4982a9a08464/abe2300-F7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/eebaea4c8ef3/abe2300-F8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a1a/8046365/7fc0f876a38b/abe2300-F9.jpg

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