Yang Hongtian, Hou Hailong, Pahng Amanda, Gu Hua, Nairn Angus C, Tang Ya-Ping, Colombo Paul J, Xia Houhui
Neuroscience Center of Excellence, School of Medicine, and.
Neuroscience Program and.
J Neurosci. 2015 Nov 11;35(45):15082-7. doi: 10.1523/JNEUROSCI.1865-15.2015.
Reversible phosphorylation, a fundamental regulatory mechanism required for many biological processes including memory formation, is coordinated by the opposing actions of protein kinases and phosphatases. Type I protein phosphatase (PP1), in particular, has been shown to constrain learning and memory formation. However, how PP1 might be regulated in memory is still not clear. Our previous work has elucidated that PP1 inhibitor-2 (I-2) is an endogenous regulator of PP1 in hippocampal and cortical neurons (Hou et al., 2013). Contrary to expectation, our studies of contextual fear conditioning and novel object recognition in I-2 heterozygous mice suggest that I-2 is a memory suppressor. In addition, lentiviral knock-down of I-2 in the rat dorsal hippocampus facilitated memory for tasks dependent on the hippocampus. Our data indicate that I-2 suppresses memory formation, probably via negatively regulating the phosphorylation of cAMP/calcium response element-binding protein (CREB) at serine 133 and CREB-mediated gene expression in dorsal hippocampus. Surprisingly, the data from both biochemical and behavioral studies suggest that I-2, despite its assumed action as a PP1 inhibitor, is a positive regulator of PP1 function in memory formation.
We found that inhibitor-2 acts as a memory suppressor through its positive functional influence on type I protein phosphatase (PP1), likely resulting in negative regulation of cAMP/calcium response element-binding protein (CREB) and CREB-activated gene expression. Our studies thus provide an interesting example of a molecule with an in vivo function that is opposite to its in vitro function. PP1 plays critical roles in many essential physiological functions such as cell mitosis and glucose metabolism in addition to its known role in memory formation. PP1 pharmacological inhibitors would thus not be able to serve as good therapeutic reagents because of its many targets. However, identification of PP1 inhibitor-2 as a critical contributor to suppression of memory formation by PP1 may provide a novel therapeutic target for memory-related diseases.
可逆磷酸化是包括记忆形成在内的许多生物过程所需的一种基本调节机制，它由蛋白激酶和磷酸酶的相反作用协调。特别是I型蛋白磷酸酶（PP1）已被证明会限制学习和记忆形成。然而，PP1在记忆中如何被调节仍不清楚。我们之前的工作已经阐明，PP1抑制剂-2（I-2）是海马体和皮层神经元中PP1的内源性调节剂（Hou等人，2013年）。与预期相反，我们对I-2杂合小鼠进行的情境恐惧条件反射和新物体识别研究表明，I-2是一种记忆抑制因子。此外，慢病毒介导的大鼠背侧海马体中I-2的敲低促进了依赖海马体的任务的记忆。我们的数据表明，I-2可能通过负向调节背侧海马体中cAMP/钙反应元件结合蛋白（CREB）丝氨酸133位点的磷酸化以及CREB介导的基因表达来抑制记忆形成。令人惊讶的是，生化和行为学研究的数据均表明，尽管I-2被认为是一种PP1抑制剂，但它在记忆形成中却是PP1功能的正向调节剂。
我们发现抑制剂-2通过对I型蛋白磷酸酶（PP1）的正向功能影响发挥记忆抑制作用，这可能导致对cAMP/钙反应元件结合蛋白（CREB）以及CREB激活的基因表达的负向调节。因此，我们的研究提供了一个有趣的例子，即一种分子的体内功能与其体外功能相反。PP1除了在记忆形成中发挥已知作用外，还在许多基本生理功能如细胞有丝分裂和葡萄糖代谢中起关键作用。因此，由于PP1有许多靶点，PP1药理学抑制剂不能作为良好的治疗试剂。然而，将PP1抑制剂-2鉴定为PP1抑制记忆形成的关键因素可能为记忆相关疾病提供一个新的治疗靶点。
