Regulation of CaMKII by α4/PP2Ac contributes to learning and memory
Abstract
Ca(2+)-dependent CaMKIIalpha activation with autophosphorylation plays an essential role in learning and memory. The regulation of CaMKIIalpha by dephosphorylation by protein phosphatase 1 (PP1) has been demonstrated. We addressed whether the protein phosphatase 2A (PP2A) that is abundant in the brain could be involved in the regulation of CaMKIIalpha. CaMKIIalpha was associated with the catalytic subunit of PP2A (PP2Ac) and alpha4, a regulator of PP2A. To investigate whether alpha4 plays an important role in the CNS, we established a neuron specific Cre transgenic mouse and a neuron specific alpha4 deficient mouse (N-alpha4 KO mouse). This N-alpha4 KO mouse showed impaired learning and memory in a water maze and also shuttle-box avoidance test. The activity of CaMKIIalpha also increased in hippocampus. An overexpression of alpha4 in the neuronal cell line demonstrated the activity of CaMKIIalpha to be regulated by alpha4. alpha4 and PP2Ac were localized in the cytoplasm but not in the postsynaptic density (PSD), thus suggesting that the dephosphorylation of CaMKIIalpha by alpha4/PP2Ac occurred in the cytoplasm. These results suggest that alpha4 and PP2A may thus play an important role in CaMKIIalpha regulation and thereby also influence learning.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Brain-specific α4 knockout mice showed impaired learning and memory (measured through spatial learning and shuttle box avoidance tests), but no sensorimotor or motivational deficiencies.
“Nevertheless, the brain-specific α4 KO mice did show impaired learning and memory (measured through spatial learning and shuttle box avoidance tests), but no sensorimotor or motivational deficiencies.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [48]
Conditional knockout of α4 in neurons did not result in any gross abnormalities in brain development, despite clearly decreased overall PP2A activity in hippocampal extracts.
“In contrast, conditional KO of α4 in neurons did not result in any gross abnormalities in brain development, despite clearly decreased overall PP2A activity in hippocampal extracts [48].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [48]
The presumed dysfunction of the hippocampus correlated with increased activity of CaMKIIα.
“The presumed dysfunction of the hippocampus correlated with increased activity of CaMKIIα [48].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [48]
Cites
THE STRUCTURE AND REGULATION OF PROTEIN PHOSPHATASES
Cohen, P. (1989) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.58.070189.002321 · Cited by 2,547 · see citing works
Janssens, V., & Goris, J. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3530417 · Cited by 1,890 · see citing works
The molecular basis of CaMKII function in synaptic and behavioural memory
Lisman, J., Schulman, H., & Cline, H. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn753 · Cited by 1,860 · see citing works
Deficient Hippocampal Long-Term Potentiation in α-Calcium-Calmodulin Kinase II Mutant Mice
Silva, A. J., Stevens, C. F., Tonegawa, S., & Wang, Y. (1992) · Science · doi:10.1126/science.1378648 · Cited by 1,472 · see citing works
Janssens, V., & Goris, J. (2001) · Biochemical Journal · doi:10.1042/bj3530417 · Cited by 1,392 · see citing works
Autophosphorylation at Thr <sup>286</sup> of the α Calcium-Calmodulin Kinase II in LTP and Learning
Giese, K. P., Fedorov, N. B., Filipkowski, R. K., & Silva, A. J. (1998) · Science · doi:10.1126/science.279.5352.870 · Cited by 1,055 · see citing works
Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth
Mumby, M. C., & Walter, G. (1993) · Physiological Reviews · doi:10.1152/physrev.1993.73.4.673 · Cited by 661 · see citing works
Serine/threonine protein phosphatases
Wera, S., & Hemmings, B. A. (1995) · Biochemical Journal · doi:10.1042/bj3110017 · Cited by 637 · see citing works
Strack, S., Barban, M. A., Wadzinski, B. E., & Colbran, R. J. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68052119.x · Cited by 299 · see citing works
Inhibitory Autophosphorylation of CaMKII Controls PSD Association, Plasticity, and Learning
Elgersma, Y., Fedorov, N. B., Ikonen, S., Choi, E. S., Elgersma, M., Carvalho, O. M., Giese, K. P., & Silva, A. J. (2002) · Neuron · doi:10.1016/s0896-6273(02)01007-3 · Cited by 290 · see citing works
Thiel, G., Czernik, A. J., Gorelick, F. S., Nairn, A. C., & Greengard, P. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.17.6337 · Cited by 176 · see citing works
Kremmer, E., Ohst, K., Kiefer, J., Brewis, N., & Walter, G. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.3.1692 · Cited by 175 · see citing works
Lou, L., & Schulman, H. (1989) · The Journal of Neuroscience · doi:10.1523/jneurosci.09-06-02020.1989 · Cited by 161 · see citing works
Molloy, S. S., & Kennedy, M. B. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.11.4756 · Cited by 132 · see citing works
Inui, S., Sanjo, H., Maeda, K., Yamamoto, H., Miyamoto, E., & Sakaguchi, N. (1998) · Blood · doi:10.1182/blood.v92.2.539.414k23_539_546 · Cited by 118 · see citing works
Self-citationRegulation of Signal Transduction by Protein Targeting: The Case for CaMKII
Bayer, K. U., & Schulman, H. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.6063 · Cited by 104 · see citing works
Fukunaga, K., Rich, D. P., & Soderling, T. R. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)88259-3 · Cited by 100 · see citing works
Self-citationBejar, R. L., Yasuda, R., Krugers, H. J., Hood, K. L., & Mayford, M. R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05719.2002 · Cited by 95 · see citing works
Decreased Protein Phosphatase 2A Activity in Hippocampal Long‐Term Potentiation
Fukunaga, K., Müller, D., Ohmitsu, M., Bakó, É., DePaoli-Roach, A. A., & Miyamoto, E. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.740807.x · Cited by 90 · see citing works
Self-citationInui, S., Kuwahara, K., Mizutani, J., Maeda, K., Kawai, T., Nakayasu, H., & Sakaguchi, N. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.6.2714 · Cited by 72 · see citing works
Self-citationAlpha4 protein as a common regulator of type 2A‐related serine/threonine protein phosphatases1
Nanahoshi, M., Tsujishita, Y., Tokunaga, C., Inui, S., Sakaguchi, N., Hara, K., & Yonezawa, K. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00189-1 · Cited by 64 · see citing works
Self-citationTakeuchi, Y., Fukunaga, K., & Miyamoto, E. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00967.x · Cited by 58 · see citing works
Self-citationSequence of the cDNA for the alpha subunit of calmodulin kinase II from mouse brain
Hanley, R. M., Payne, M. E., Cruzalegui, F. H., Christenson, M. A., & Means, A. R. (1989) · Nucleic Acids Research · doi:10.1093/nar/17.10.3992 · Cited by 28 · see citing works
Inui, S., Maeda, K., Hua, D. R., Yamashita, T., Yamamoto, H., Miyamoto, E., Aizawa, S., & Sakaguchi, N. (2002) · International Immunology · doi:10.1093/intimm/14.2.177 · Cited by 19 · see citing works
Self-citationT cell‐specific gene targeting reveals that α4 is required for early T cell development
Hua, D. R., Inui, S., Yamashita, T., Maeda, K., Takagi, K., Takeda, J., & Sakaguchi, N. (2003) · European Journal of Immunology · doi:10.1002/eji.200323720 · Cited by 16 · see citing works
Self-citationMaeda, K., Inui, S., Tanaka, H., & Sakaguchi, N. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00571.x · Cited by 16 · see citing works
Self-citationHigo, S., Matsuyama, T., & Kawamura, S. (1996) · Neuroscience Research · doi:10.1016/s0168-0102(96)01079-6 · Cited by 14 · see citing works
Sasaki, H., Inoue, T., Iso, H., & Fukuda, Y. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7183 · Cited by 14 · see citing works
Yukawa, K., Tanaka, T., Toyomi, A., Tsuji, S., Akira, S., & Iso, H. (2000) · Neuroscience Research Communications · doi:10.1002/(sici)1520-6769(200001/02)26:1 · Cited by 3 · see citing works
T cell-specific gene targeting reveals that α4 is required for early T cell development
丁, 栄. (2003) · Medical Entomology and Zoology · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
An integrated workflow for charting the human interaction proteome: insights into the PP2A system
Glatter, T., Wepf, A., Aebersold, R. H., & Gstaiger, M. (2009) · Molecular Systems Biology · doi:10.1038/msb.2008.75 · Cited by 259 · see citing works
Protein phosphatase 2A regulatory subunits and cancer
Eichhorn, P. J. A., Creyghton, M. P., & Bernards, R. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.05.005 · Cited by 513 · see citing works
Tucker, B., Richards, R. I., & Lardelli, M. T. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl422 · Cited by 133 · see citing works
Physiologic functions of PP2A: Lessons from genetically modified mice
Reynhout, S., & Janssens, V. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.07.010 · Cited by 124 · see citing works
Rahman, A., Khan, K. M., Al‐Khaledi, G., Khan, I., & Al-Shemary, T. E. (2012) · NeuroToxicology · doi:10.1016/j.neuro.2012.02.014 · Cited by 48 · see citing works
Lead Dysregulates Serine/Threonine Protein Phosphatases in Human Neurons
Rahman, A., Brew, B. J., & Guillemin, G. J. (2010) · Neurochemical Research · doi:10.1007/s11064-010-0300-6 · Cited by 48 · see citing works
Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease
Verbinnen, I., Vaneynde, P., Reynhout, S., Lenaerts, L., Derua, R., Houge, G., & Janssens, V. (2021) · Biochemical Society Transactions · doi:10.1042/bst20201313 · Cited by 48 · see citing works
Role of protein phosphatases and mitochondria in the neuroprotective effects of estrogens
Simpkins, J. W., Yi, K. D., & Yang, S. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.04.013 · Cited by 48 · see citing works
Charles, P. D., Singh, H. K., Jayakumar, P., & Rajan, K. E. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23080 · Cited by 48 · see citing works
Wang, J., Lou, S., Wang, T., Wu, R., Li, G., Zhao, M., Lü, B., Li, Y., Zhang, J., Cheng, X., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820131116 · Cited by 47 · see citing works
Regulation of CaMKII In vivo: The Importance of Targeting and the Intracellular Microenvironment
Skelding, K. A., & Rostas, J. A. P. (2009) · Neurochemical Research · doi:10.1007/s11064-009-9985-9 · Cited by 37 · see citing works
Enhancing memory formation by altering protein phosphorylation balance
Rosenegger, D. G., Parvez, K., & Lukowiak, K. (2008) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2008.06.005 · Cited by 34 · see citing works
Smetana, J. H. C., & Zanchin, N. I. T. (2007) · FEBS Journal · doi:10.1111/j.1742-4658.2007.06112.x · Cited by 35 · see citing works
Jayakumar, P., Singh, H. K., Venkataraman, J. S., & Rajan, K. E. (2014) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-014-0042-0 · Cited by 28 · see citing works
A protein phosphatase 2A deficit in the hippocampal CA1 area impairs memory extinction
Wang, J., Xie, R., Kou, X., Liu, Y., Cui, Q., Liu, R., You, W., Gao, J., & Gao, X. (2019) · Molecular Brain · doi:10.1186/s13041-019-0469-9 · Cited by 27 · see citing works
<i>α</i> 4 Coordinates Small Intestinal Epithelium Homeostasis by Regulating Stability of HuR
Chung, H. K., Wang, S. R., Xiao, L., Rathor, N., Turner, D. J., Yang, P., Gorospe, M., Rao, J. N., & Wang, J.-Y. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00631-17 · Cited by 26 · see citing works
Hilal, M. L., Moreau, M. M., Racca, C., Pinheiro, V. L., Piguel, N. H., Santoni, M.-J., Dos Santos Carvalho, S., Blanc, J.-M., Abada, Y.-S. K., Peyroutou, R., et al. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhw333 · Cited by 20 · see citing works
Review of PP2A Tumor Biology and Antitumor Effects of PP2A Inhibitor LB100 in the Nervous System
Bryant, J.-P., Levy, A. S., Heiss, J. D., & Banasavadi‐Siddegowda, Y. (2021) · Cancers · doi:10.3390/cancers13123087 · Cited by 19 · see citing works
CaMKII phosphorylates serine 10 of p27 and confers apoptosis resistance to HeLa cells
Kajihara, R., Fukushige, S., Shioda, N., Tanabe, K., Fukunaga, K., & Inui, S. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.09.051 · Cited by 18 · see citing works
Self-citationRadwańska, K., Jones, A. A. T., Mizuno, K., Pereira, G. S., Lucchesi, W., Alfano, I., Lach, A. A., Kaczmarek, L., Knapp, S., & Giese, K.-P. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00595.x · Cited by 16 · see citing works
Zhang, M., Zhai, Y., Sun, Y., Zhang, W., Li, Q., Brann, D. W., & Wang, R. (2018) · Brain Research · doi:10.1016/j.brainres.2018.05.020 · Cited by 16 · see citing works
Hwang, Y., Kim, H., & Shin, E. (2021) · Toxicology · doi:10.1016/j.tox.2021.152887 · Cited by 16 · see citing works
Regulation of Multifunctional Calcium/Calmodulin Stimulated Protein Kinases by Molecular Targeting
Skelding, K. A., & Rostas, J. A. P. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12457-1_26 · Cited by 13 · see citing works
CaMKII protects MKP-1 from proteasome degradation in endothelial cells
Ciccarelli, M., Rusciano, M. R., Sorriento, D., Basilicata, M. F., Santulli, G., Campiglia, P., Bertamino, A., LUCA, N. D., Trimarco, B., Iaccarino, G., et al. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.06.009 · Cited by 11 · see citing works
Wang, N., Leung, H., Mazalouskas, M. D., Watkins, G. R., Gomez, R. J., & Wadzinski, B. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038569 · Cited by 11 · see citing works
Progesterone regulates the phosphorylation of protein phosphatases in the brain
Amorim, M. A. R., Guerra‐Araiza, C., Pernía, O., Silva, E. F. D. C. E., & García‐Segura, L. M. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22442 · Cited by 11 · see citing works
Mucic, G., Sase, S., Stork, O., Lübec, G., & Li, L. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.11.024 · Cited by 10 · see citing works
Rahman, A., & Guillemin, G. J. (2021) · Springer eBooks · doi:10.1007/978-3-030-71519-9_142-1 · Cited by 8 · see citing works
Elamin, M., Lemtiri‐Chlieh, F., Robinson, T. M., & Levine, E. S. (2023) · Epilepsia · doi:10.1111/epi.17687 · Cited by 8 · see citing works
Lee, D.-S., Kim, T. H., Park, H., & Kim, J.-E. (2023) · Scientific Reports · doi:10.1038/s41598-023-41014-7 · Cited by 6 · see citing works
Cheng, X., He, S., Liang, X., Song, Y., Yuan, X., Li, L., Wen, Z., Cai, W.-J., & Tao, Y. (2015) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2015.08.001 · Cited by 5 · see citing works
Shi, L.-J., Li, J., Liang, X., He, S., Dou, Y., Peng, J., Cai, W., & Liang, H. (2021) · Fish Physiology and Biochemistry · doi:10.1007/s10695-021-01001-z · Cited by 4 · see citing works
Postsynaptic Targeting of Protein Kinases and Phosphatases
Strack, S., & Hell, J. W. (2008) · Springer eBooks · doi:10.1007/978-0-387-77232-5_16 · Cited by 3 · see citing works
Rahman, A. (2014) · Springer eBooks · doi:10.1007/978-1-4614-5836-4_142 · Cited by 1 · see citing works
Ogata, G., Partida, G. J., Fasoli, A., & Ishida, A. T. (2022) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2022.958986 · Cited by 1 · see citing works
Rahman, A., & Guillemin, G. J. (2022) · Springer eBooks · doi:10.1007/978-3-031-15080-7_142 · Cited by 1 · see citing works
Gene Expression Profiles in GP160-Expressing Mouse Model of HIV-Associated Dementia
Ghorbani, M., & Sedigheh, H.-G. (2012)
Conditional Gene Targeting: A Refined Method for Genetic Studies in Neurosciences
Beil, J., Mansuy, I. M., & Buch, T. (2013) · Neuromethods · doi:10.1007/978-1-62703-517-0_1
Dendritic Protein Phosphatase Complexes
Baucum, A. J., & Colbran, R. J. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00167-4
- Authors
- Yamashita, T., Inui, S., Maeda, K., Hua, D. R., Takagi, K., Fukunaga, K., & Sakaguchi, N.
- Affiliations
- Kumamoto University (JP)
- Tohoku University (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Sakaguchi, Nobuo
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 1082
- Issue
- 1
- Pages
- 1-10
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2046287986
- Cited by
- 41
- References
- 29
- Citations by year
- 2023: 2 · 2022: 2 · 2021: 5 · 2019: 3 · 2018: 3 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 4
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CaMKIIα, protein phosphatase 2A, PP2A catalytic subunit, dephosphorylation, autophosphorylation, learning and memory, hippocampus, postsynaptic density
- MeSH terms
- Analysis of Variance, Animals, Avoidance Learning, Behavior, Animal, Brain, Enzyme Activation, Gene Expression Regulation, Learning, Mice, Inbred C57BL, Neuroblastoma, Phosphoprotein Phosphatases, Phosphoproteins, Reaction Time, Transfection, Blotting, Western, Calcium-Calmodulin-Dependent Protein Kinases, Mice, Knockout, Maze Learning, Molecular Chaperones, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice, Protein Phosphatase 1, Protein Phosphatase 2, Calcium-Calmodulin-Dependent Protein Kinase Type 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review