An ultrasensitive Ca 2+ /calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling
Open accessAbstract
The strength of hippocampal synapses can be persistently increased by signals that activate Ca2+/calmodulin-dependent protein kinase II (CaMKII). This CaMKII-dependent long-term potentiation is important for hippocampal learning and memory. In this work we show that CaMKII exhibits an intriguing switch-like activation that likely is important for changes in synaptic strength. We found that autophosphorylation of CaMKII by itself showed a steep dependence on Ca2+ concentration [Hill coefficient (nH) approximately 5]. However, an even steeper Ca2+ dependence (nH approximately 8) was observed when autophosphorylation is balanced by the dephosphorylation activity of protein phosphatase 1 (PP1). This autophosphorylation-dephosphorylation switch was found to be reversible because PP1 dephosphorylates CaMKII when Ca2+ is lowered to a basal level. The switch-like response of a CaMKII-PP1 system suggests that CaMKII and PP1 may function together as a simple molecular device that specifically translates only strong Ca2+ signals into all-or-none potentiation of individual hippocampal synapses.
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The apparent Kd of CaMKII for Ca2+ for autophosphorylation is 1.6 μM when CaM is not limiting.
“The low affinity of CaMKII for Ca2+ when CaM is not limiting (apparent Kd = 1.6 µM for autophosphorylation) (108)”
From Synaptic memory and CaMKII (2023) · cites this paper as [108]
The affinity of CaMKII for Ca2+/CaM is far lower than that of the average Ca2+/CaM-dependent enzyme; Kd values are calcineurin 28 pM, MLCK 5.1 nM, CaMKII 51 nM, and CaMKII(T286P) 7.6 pM.
“The affinity for Ca2+/CaM is (at saturating Ca2+) far lower than the average Ca2+/CaM-dependent enzyme, e.g., Kd for CaM interaction with calcineurin = 28 pM; myosin light chain kinase (MLCK) = 5.1 nM; CaMKII = 51 nM; and CaMKII (T286P) = 7.6 pM (108, 114).”
From Synaptic memory and CaMKII (2023) · cites this paper as [108]
CaMKII has an unusually high Hill coefficient of approximately 6.
“and the unusually high Hill coefficient of ∼6 for CaMKII (108)”
From Synaptic memory and CaMKII (2023) · cites this paper as [108]
The unusually high Hill coefficient of ∼6 for CaMKII and the high requirement for Ca2+ compared to resting Ca2+ ensures maintenance of synapse specificity and the Hebbian nature of LTP.
“The unusually high Hill coefficient of ∼6 for CaMKII (108) and the high requirement for Ca2+ (half maximal of ∼1.6 µM at saturating CaM) compared to the resting level of Ca2+ (20–50 nM) (109, 110) ensures maintenance of the synapse specificity and Hebbian nature of LTP (19).”
From Synaptic memory and CaMKII (2023) · cites this paper as [108]
Cites
Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression
Mulkey, R. M., Endo, S., Shenolikar, S., & Malenka, R. C. (1994) · Nature · doi:10.1038/369486a0 · Cited by 1,083 · see citing works
Interaction with the NMDA receptor locks CaMKII in an active conformation
Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., & Schulman, H. (2001) · Nature · doi:10.1038/35081080 · Cited by 732 · see citing works
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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 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
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Mechanisms Underlying the Rules for Associative Plasticity at Adult Human Neocortical Synapses
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“The af fi nity for Ca 2 1 /CaM is (at saturating Ca 2 1 ) far lower than the average Ca 2 1 /CaM-dependent enzyme, e.g., K d for CaM interaction with calcineurin ¼ 28 pM; myosin light chain kinase (MLCK) ¼ 5.1 nM; CaMKII ¼ 51 nM; and CaMKII (T286P) ¼ 7.6 pM (108, 114).”
BackgroundInfluentialSelf-citationIntersubunit 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
Self-citationSmolen, P., Baxter, D. A., & Byrne, J. H. (2006) · Biophysical Journal · doi:10.1529/biophysj.105.072470 · Cited by 61 · see citing works
Regulation of cytoplasmic polyadenylation can generate a bistable switch
Aslam, N., & Shouval, H. Z. (2012) · BMC Systems Biology · doi:10.1186/1752-0509-6-12 · Cited by 11 · see citing works
- Authors
- Bradshaw, J. M., Kubota, Y., Meyer, T., & Schulman, H.
- Affiliations
- Stanford Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-08-19
- Volume
- 100
- Issue
- 18
- Pages
- 10512-10517
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC193592
- OpenAlex
- W2144948613
- Cited by
- 189
- References
- 2
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 7 · 2017: 3 · 2016: 9 · 2015: 6 · 2014: 12 · 2013: 15 · 2012: 10
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Jane Coffin Childs Memorial Fund for Medical Research
- National Institutes of Health (2r01gm040600-10)
- National Institute of General Medical Sciences (R01GM030179, GM40600, GM 30179, R37GM030179)
- Topics
- 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
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- CaMKII, protein phosphatase 1, autophosphorylation, dephosphorylation, switch-like response, Hill coefficient, calcium signaling, long-term potentiation, hippocampal synapses, synaptic plasticity
- MeSH terms
- Hippocampus, Phosphoprotein Phosphatases, Phosphorylation, Synapses, Calcium-Calmodulin-Dependent Protein Kinases, Calcium Signaling, Protein Phosphatase 1, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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