Department of Pathology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Hippocampus. 2012 Jul;22(7):1501-7. doi: 10.1002/hipo.20996. Epub 2011 Dec 23.
The persistent activity of protein kinase Mzeta (PKMζ), a brain-specific, constitutively active protein kinase C isoform, maintains synaptic long-term potentiation (LTP). Structural remodeling of the postsynaptic density is believed to contribute to the expression of LTP. We therefore examined the role of PKMζ in reconfiguring PSD-95, the major postsynaptic scaffolding protein at excitatory synapses. In primary cultures of hippocampal neurons, PKMζ activity was critical for increasing the size of PSD-95 clusters during chemical LTP (cLTP). Increasing PKMζ activity by overexpressing the kinase in hippocampal neurons was sufficient to increase PSD-95 cluster size, spine size, and postsynaptic AMPAR subunit GluA2. Overexpression of an inactive mutant of PKMζ did not increase PSD-95 clustering, and applications of the ζ-pseudosubstrate inhibitor ZIP reversed the PKMζ-mediated increases in PSD-95 clustering, indicating that the activity of PKMζ is necessary to induce and maintain the increased size of PSD-95 clusters. Thus the persistent activity of PKMζ is both necessary and sufficient for maintaining increases of PSD-95 clusters, providing a unified mechanism for long-term functional and structural modifications of synapses.
蛋白激酶 Mzeta（PKMζ）是一种脑特异性、组成型激活的蛋白激酶 C 同工型，其持续活性维持着突触长时程增强（LTP）。人们认为突触后密度的结构重塑有助于 LTP 的表达。因此，我们研究了 PKMζ 在重新配置 PSD-95（兴奋性突触后主要支架蛋白）中的作用。在海马神经元的原代培养物中，PKMζ 活性对于化学长时程增强（cLTP）过程中 PSD-95 簇的增大至关重要。通过在海马神经元中过表达激酶来增加 PKMζ 活性足以增加 PSD-95 簇的大小、棘突的大小和突触后 AMPAR 亚基 GluA2。过表达 PKMζ 的无活性突变体不会增加 PSD-95 聚类，并且 ζ-假底物抑制剂 ZIP 的应用逆转了 PKMζ 介导的 PSD-95 聚类增加，表明 PKMζ 的活性对于诱导和维持 PSD-95 聚类的增加是必要的。因此，PKMζ 的持续活性对于维持 PSD-95 簇的增加是必要且充分的，为突触的长期功能和结构修饰提供了统一的机制。
