Department of Pharmacology, University of Colorado - Anschutz Medical Campus, Aurora, USA.
Department of Pharmacology, University of Colorado - Anschutz Medical Campus, Aurora, USA.
J Biol Chem. 2022 Sep;298(9):102299. doi: 10.1016/j.jbc.2022.102299. Epub 2022 Jul 21.
The Ca/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear. Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation (pT286), which induces Ca-independent autonomous kinase activity. In addition, we compared the role of pT286 among three forms of long-term plasticity (NMDAR-dependent LTP and LTD, and mGluR-dependent LTD) using simultaneous live imaging of endogenous CaMKII together with synaptic marker proteins. We determined that after LTP stimuli, pT286 autophosphorylation accelerated CaMKII movement to excitatory synapses. After NMDAR-LTD stimuli, pT286 was strictly required for any movement to inhibitory synapses. Similar to NMDAR-LTD, we found the mGluR-LTD stimuli did not induce CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, we demonstrate that the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Thus, despite its prominent role in LTP, we conclude that CaMKII T286 autophosphorylation is also required for both major forms of hippocampal LTD, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.
钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）介导海马 NMDA 型谷氨酸受体（NMDAR）不同刺激后的长时程增强或抑制（LTP 或 LTD）。NMDA 受体依赖性 LTD 在幼年小鼠中占主导地位，但通过刺激代谢型谷氨酸受体（mGluR）可以很容易地在成年小鼠中诱导出一种机制上不同的 LTD 形式。然而，CaMKII 在 mGluR 依赖性 LTD 中的作用尚不清楚。在这里，我们表明 mGluR 依赖性 LTD 也需要 CaMKII 和其 T286 自身磷酸化（pT286），这诱导了 Ca 独立的自主激酶活性。此外，我们通过同时对内源性 CaMKII 与突触标记蛋白进行实时成像，比较了三种长时程可塑性形式（NMDAR 依赖性 LTP 和 LTD 以及 mGluR 依赖性 LTD）中 pT286 的作用。我们确定，在 LTP 刺激后，pT286 自身磷酸化加速了 CaMKII 向兴奋性突触的运动。在 NMDAR-LTD 刺激后，pT286 严格需要任何向抑制性突触的运动。与 NMDAR-LTD 相似，我们发现 mGluR-LTD 刺激不会诱导 CaMKII 向兴奋性突触运动。然而，与 NMDAR-LTD 相反，我们证明 mGluR-LTD 不涉及 CaMKII 向抑制性突触的运动，也不需要额外的 T305/306 自身磷酸化。因此，尽管 CaMKII 在 LTP 中起重要作用，但我们得出结论，CaMKII T286 自身磷酸化对于海马 LTD 的两种主要形式也是必需的，尽管对兴奋性信号到抑制性突触的异突触通讯有不同的要求。
