Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
J Biol Chem. 2012 Apr 13;287(16):12879-85. doi: 10.1074/jbc.M112.357244. Epub 2012 Feb 29.
A number of recent studies have used pharmacological inhibitors to establish a role for protein kinase Mζ (PKMζ) in synaptic plasticity and memory. These studies use zeta inhibitory peptide (ZIP) and chelerythrine as inhibitors of PKMζ to block long term potentiation and memory; staurosporine is used as a negative control to show that a nonspecific kinase inhibitor does not block long term potentiation and memory. Here, we show that neither ZIP nor chelerythrine inhibits PKMζ in cultured cells or brain slices. In contrast, staurosporine does block PKMζ activity in cells and brain slices by inhibiting its upstream phosphoinositide-dependent kinase-1. These studies demonstrate that the effectiveness of drugs against purified PKMζ may not be indicative of their specificity in the more complex environment of the cell and suggest that PKMζ is unlikely to be the mediator of synaptic plasticity or memory.
近年来的一些研究使用药理学抑制剂来确定蛋白激酶 Mζ（PKMζ）在突触可塑性和记忆中的作用。这些研究使用 ζ 抑制肽（ZIP）和石杉碱甲作为 PKMζ 的抑制剂来阻断长时程增强和记忆；使用 staurosporine 作为阴性对照，以表明非特异性激酶抑制剂不会阻断长时程增强和记忆。在这里，我们表明 ZIP 和石杉碱甲都不能抑制培养细胞或脑片中的 PKMζ。相比之下，staurosporine 通过抑制其上游的磷酸肌醇依赖性激酶-1 来阻断细胞和脑片中的 PKMζ 活性。这些研究表明，药物对纯化的 PKMζ 的有效性可能不能说明它们在细胞更复杂环境中的特异性，并且表明 PKMζ 不太可能是突触可塑性或记忆的介导者。
