Stimulating β-adrenergic receptors promotes synaptic potentiation by switching CaMKII movement from LTD to LTP mode.
Stimulating β-adrenergic receptors promotes synaptic potentiation by switching CaMKII movement from LTD to LTP mode.
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DOI：
10.1016/j.jbc.2023.104706
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发表时间：
2023-06
影响因子：
4.8
通讯作者：
Bayer, K Ulrich
中科院分区：
文献类型：
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作者：
Larsen, Matthew E;Buonarati, Olivia R;Qian, Hai;Hell, Johannes W;Bayer, K Ulrich
学习、记忆和认知被认为需要突触可塑性，特别是海马长时程增强和抑制（LTP 和 LTD）。 LTP 与 LTD 是由高频刺激与低频刺激诱导的，但刺激 β-肾上腺素能受体 (βAR) 也可以通过低频刺激 (1 Hz) 或 θ 频率 (∼5 Hz) 诱导 LTP，而这些刺激本身不会引起可塑性。与高频刺激 LTP 相比，这种 βAR-LTP 需要通过 L 型电压门控 Ca2+ 通道的 Ca2+ 通量，而不是 N-甲基-D-天冬氨酸型谷氨酸受体。令人惊讶的是，我们发现 βAR-LTP 仍然需要 N-甲基-D-天冬氨酸型谷氨酸受体的非离子型支架功能：刺激诱导的 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 与其 GluN2B 亚基的结合，介导 CaMKII 向兴奋性突触的运动。在海马神经元中，异丙肾上腺素 (Iso) 的 β-肾上腺素能刺激将 LTD 型 CaMKII 运动转变为 LTP 型运动，导致 CaMKII 运动为兴奋性而非抑制性突触。此外，Iso 能够诱导 LTP 响应 LTD 刺激的主要细胞生物学特征：与超黄道 pHluorein 融合的 GluA1 表面表达增加。与海马切片中的 βAR-LTP 一样，Iso 对 CaMKII 运动和与超黄道 pHluorein 融合的 GluA1 表面表达的影响涉及 L 型 Ca2+ 通道和特别需要的 β2-AR。综上所述，这些结果表明 Iso 通过将 CaMKII 运动和 GluN2B 结合切换为 LTP 模式，将 LTD 刺激转化为 LTP 信号。
Learning, memory, and cognition are thought to require synaptic plasticity, specifically including hippocampal long-term potentiation and depression (LTP and LTD). LTP versus LTD is induced by high-frequency stimulation versus low-frequency, but stimulating β-adrenergic receptors (βARs) enables LTP induction also by low-frequency stimulation (1 Hz) or theta frequencies (∼5 Hz) that do not cause plasticity by themselves. In contrast to high-frequency stimulation-LTP, such βAR-LTP requires Ca2+-flux through L-type voltage-gated Ca2+-channels, not N-methyl-D-aspartate–type glutamate receptors. Surprisingly, we found that βAR-LTP still required a nonionotropic scaffolding function of the N-methyl-D-aspartate–type glutamate receptor: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) to its GluN2B subunit that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, β-adrenergic stimulation with isoproterenol (Iso) transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, Iso enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased surface expression of GluA1 fused with super-ecliptic pHluorein. Like for βAR-LTP in hippocampal slices, the Iso effects on CaMKII movement and surface expression of GluA1 fused with super-ecliptic pHluorein involved L-type Ca2+-channels and specifically required β2-ARs. Taken together, these results indicate that Iso transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode.