Regulation of brain Type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: A Ca2+-triggered molecular switch
Abstract
Calcium/calmodulin-stimulated autophosphorylation of a prominent brain calmodulin-dependent protein kinase (Type II CaM kinase) produces dramatic changes in its enzymatic activity. These changes suggest a mechanism by which the kinase could act as a calcium-triggered molecular switch. Incorporation of 3-12 of a possible total of 30 phosphate groups per holoenzyme causes kinase activity toward exogenous substrates as well as autophosphorylation itself to become independent of calcium. Thus, kinase activity could be prolonged beyond the duration of an initial activating calcium signal. The calcium-independent autophosphorylation could further prolong the active state by opposing dephosphorylation by cellular phosphatases.
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?
CaMKII becomes independent of Ca2+ (autonomous) after autophosphorylation.
“it was not until the discovery of a Ca2+/calmodulin-dependent protein kinase, now referred to as CaMKII (9, 10), which became independent of Ca2+ (autonomous) after autophosphorylation (11–15)”
From Synaptic memory and CaMKII (2023) · cites this paper as [15]
CaMKII exhibits switchlike autonomy after autophosphorylation of just a minority of its subunits.
“and exhibited switchlike autonomy after autophosphorylation of just a minority of its subunits (15)”
From Synaptic memory and CaMKII (2023) · cites this paper as [15]
Once activated by Ca2+, CaMKII enzymatic activity toward substrates remains after Ca2+ removal.
“Fourth, CaMKII has the intriguing property that once activated by Ca2+ the enzymatic activity toward substrates remains after Ca2+ removal (11–15).”
From Synaptic memory and CaMKII (2023) · cites this paper as [15]
The subunit being phosphorylated apparently needs to have Ca2+/CaM bound; phosphorylation does not significantly occur on inactive subunits.
“A further complication for either of these possibilities is that it appears that the subunit being phosphorylated apparently would need to have Ca2+/CaM bound, i.e., it does not significantly occur on inactive subunits (13, 15, 82, 83, 406).”
From Synaptic memory and CaMKII (2023) · cites this paper as [15]
Cites
Neurobiology: Memory and molecular turnover
Crick, F. (1984) · Nature · doi:10.1038/312101a0 · Cited by 392 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Emergent Properties of Networks of Biological Signaling Pathways
Bhalla, U. S., & Iyengar, R. (1999) · Science · doi:10.1126/science.283.5400.381 · Cited by 1,686 · see citing works
Control of memory formation through regulated expression of a CaMKII transgene
Mayford, M., Bach, M. E., Huang, Y.-Y., Wang, L., Hawkins, R. D., & Kandel, E. R. (1996) · Science · doi:10.1126/science.274.5293.1678 · Cited by 1,550 · see citing works
Regulation of Gene Expression in Hippocampal Neurons by Distinct Calcium Signaling Pathways
Bading, H., Ginty, D. D., & Greenberg, M. E. (1993) · Science · doi:10.1126/science.8097060 · Cited by 1,157 · see citing works
Mechanisms of CaMKII action in long-term potentiation
Lisman, J., Yasuda, R., & Raghavachari, S. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3192 · Cited by 1,134 · see citing works
Structure–function of the multifunctional Ca2+/calmodulin-dependent protein kinase II
HUDMON, A., & SCHULMAN, H. (2002) · Biochemical Journal · doi:10.1042/bj20020228 · Cited by 615 · see citing works
Shen, K., Teruel, M. N., Subramanian, K., & Meyer, T. (1998) · Neuron · doi:10.1016/s0896-6273(00)80569-3 · Cited by 350 · see citing works
Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis of the Holoenzyme
Rosenberg, O. S., Deindl, S., Sung, R.-J., Nairn, A. C., & Kuriyan, J. (2005) · Cell · doi:10.1016/j.cell.2005.10.029 · Cited by 333 · see citing works
Pettit, D. L., Perlman, S., & Malinow, R. (1994) · Science · doi:10.1126/science.7997883 · Cited by 329 · see citing works
Lai, Y., Nairn, A. C., & Greengard, P. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.12.4253 · Cited by 292 · see citing works
Rellos, P., Pike, A. C. W., Niesen, F. H., Salah, E., Lee, W. H., von Delft, F., & Knapp, S. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000426 · Cited by 279 · see citing works
The impact of postsynaptic calcium on synaptic transmission — its role in long-term potentiation
Malenka, R. C., Kauer, J. A., Perkel, D. J., & Nicoll, R. A. (1989) · Trends in Neurosciences · doi:10.1016/0166-2236(89)90094-5 · Cited by 275 · see citing works
Synaptic Signaling in Learning and Memory
Kennedy, M. B. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016824 · Cited by 270 · see citing works
Long-term potentiation: outstanding questions and attempted synthesis
Lisman, J. (2003) · Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences · doi:10.1098/rstb.2002.1242 · Cited by 240 · see citing works
Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism
Yuen, E. Y. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1187-05.2005 · Cited by 225 · see citing works
Liu, X. B., & Jones, E. G. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.14.7332 · Cited by 208 · see citing works
Miller, P., Zhabotinsky, A. M., Lisman, J. E., & Wang, X.-J. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030107 · Cited by 199 · see citing works
Incontro, S., Díaz-Alonso, J., Iafrati, J., Vieira, M., Asensio, C. S., Sohal, V. S., Roche, K. W., Bender, K. J., & Nicoll, R. A. (2018) · Nature Communications · doi:10.1038/s41467-018-04439-7 · Cited by 171 · see citing works
Patton, B. L., Miller, S. G., & Kennedy, M. B. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38577-1 · Cited by 165 · see citing works
Self-citationCytoskeletal signaling: is memory encoded in microtubule lattices by CaMKII phosphorylation?
Craddock, T. J. A., Tuszynski, J. A., & Hameroff, S. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002421 · Cited by 160 · see citing works
Buard, I., Coultrap, S. J., Freund, R. K., Lee, Y.-S., Dell'Acqua, M. L., Silva, A. J., & Bayer, K. U. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1469-10.2010 · Cited by 160 · see citing works
Regulation of NMDA Receptors by Dopamine D<sub>4</sub>Signaling in Prefrontal Cortex
Wang, X., Zhong, P., Gu, Z., & Yan, Z. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-30-09852.2003 · Cited by 159 · see citing works
Learning mechanisms: the case for CaM-KII
Lisman, J., Malenka, R. C., Nicoll, R. A., & Malinow, R. (1997) · Science · doi:10.1126/science.276.5321.2001 · Cited by 147 · see citing works
Shifman, J. M., Choi, M. H., Mihalas, S., Mayo, S. L., & Kennedy, M. B. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606433103 · Cited by 143 · see citing works
Pi, H. J., Otmakhov, N., Lemelin, D., De Koninck, P., & Lisman, J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0133-10.2010 · Cited by 125 · see citing works
Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
“Although the data are convincing, it remains unclear why previous biochemical studies (15, 82, 406, 411, 412) failed to detect interholoenzyme autophosphorylation even when hol-oenzymes were incubated at high concentrations and standard assay temperature (411, 412).”
BackgroundResultInfluentialIs Persistent Activity of Calcium/Calmodulin-Dependent Kinase Required for the Maintenance of LTP?
Chen, H.-X., Otmakhov, N., Strack, S., Colbran, R. J., & Lisman, J. E. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.85.4.1368 · Cited by 126 · see citing works
Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress
Xu, Y., Lin, D., Li, S., Li, G., Shyamala, S. G., Barish, P. A., Vernon, M. M., Pan, J., & Ogle, W. O. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.06.010 · Cited by 119 · see citing works
Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation
Chao, L. H., Pellicena, P., Deindl, S., Barclay, L. A., Schulman, H., & Kuriyan, J. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1751 · Cited by 119 · see citing works
A Peptide Model for Calmodulin Trapping by Calcium/Calmodulin-dependent Protein Kinase II
Putkey, J. A., & Waxham, M. N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.47.29619 · Cited by 94 · see citing works
Pepke, S., Kinzer-Ursem, T., Mihalas, S., & Kennedy, M. B. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000675 · Cited by 92 · see citing works
CA1 Long-Term Potentiation Is Diminished but Present in Hippocampal Slices from α-CaMKII Mutant Mice
Hinds, H. L., Tonegawa, S., & Malinow, R. (1998) · Learning & Memory · doi:10.1101/lm.5.4.344 · Cited by 86 · see citing works
Yoshimura, Y., Aoi, C., & Yamauchi, T. (2000) · Molecular Brain Research · doi:10.1016/s0169-328x(00)00170-4 · Cited by 72 · see citing works
Miller, C. A., & Sweatt, J. D. (2006) · Learning & Memory · doi:10.1101/lm.304606 · Cited by 53 · see citing works
Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction
Perfitt, T. L., Wang, X., Dickerson, M. T., Stephenson, J. R., Nakagawa, T., Jacobson, D. A., & Colbran, R. J. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0893-19.2020 · Cited by 54 · see citing works
Gu, Z., & Yan, Z. (2004) · Molecular Pharmacology · doi:10.1124/mol.104.001404 · Cited by 41 · see citing works
Gu, Z., Jiang, Q., Yuen, E. Y., & Yan, Z. (2006) · Molecular Pharmacology · doi:10.1124/mol.105.018853 · Cited by 35 · see citing works
Serotonergic neuromodulation of synaptic plasticity
Higa, G. S. V., Viana, F. J. C., Francis-Oliveira, J., Cruvinel, E., Franchin, T. S., Marcourakis, T., Ulrich, H., & De Pasquale, R. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110036 · Cited by 29 · see citing works
Synaptic memory survives molecular turnover
Lee, J., Chen, X., & Nicoll, R. A. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211572119 · Cited by 27 · see citing works
Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure
Wang, X., Gu, Z., Zhong, P., Chen, G., Feng, J., & Yan, Z. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.08.018 · Cited by 16 · see citing works
Kabakov, A. Y., & Lisman, J. E. (2015) · PLOS ONE · doi:10.1371/journal.pone.0123718 · Cited by 13 · see citing works
- Authors
- Miller, S.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Miller, S
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1986-03-28
- Volume
- 44
- Issue
- 6
- Pages
- 861-870
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2033942553
- Cited by
- 864
- References
- 1
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 9 · 2023: 11 · 2022: 14 · 2021: 16 · 2020: 16 · 2019: 20 · 2018: 11 · 2017: 14 · 2016: 10 · 2015: 17 · 2014: 25 · 2013: 14 · 2012: 23
- FWCI
- 20.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (IT32 GM07616)
- National Institute of Neurological Disorders and Stroke (NS-17660)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- calcium/calmodulin-dependent protein kinase II, autophosphorylation, calcium signaling, molecular switches, kinase regulation, dephosphorylation, phosphatase, brain
- MeSH terms
- Animals, Brain, Calcium, Calmodulin, Centrifugation, Density Gradient, Egtazic Acid, Magnesium, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Kinases, Time Factors, Rats
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
