Autonomous CaMKII can promote either long-term potentiation or long-term depression, depending on the state of T305/T306 phosphorylation
Open accessAbstract
Ca(2+)/calmodulin-dependent kinase II (CaMKII) is a key mediator of long-term potentiation (LTP). Whereas acute intracellular injection of catalytically active CaMKII fragments saturates LTP (Lledo et al., 1995), an autonomously active form (T286D) of CaMKII holoenzyme expressed in transgenic mice did not saturate potentiation (Mayford et al., 1995). To better understand the role of the holoenzyme in the control of synaptic strength, we transfected hippocampal neurons with constructs encoding forms of CaMKII mimicking different phosphorylation states. Surprisingly, T286D not only failed to potentiate synaptic strength, but produced synaptic depression through an long-term depression (LTD)-like process. T305/T306 phosphorylation was critical for this depression because overexpression of the pseudophosphorylated form (T286D/T305D/T306D) caused depression that occluded LTD, and overexpression of an autonomous form in which T305/T306 could not be phosphorylated (T286D/T305A/T306A) prevented LTD (instead producing potentiation). Therefore, autonomous CaMKII can lead to either LTP or LTD, depending on the phosphorylation state of the control point, T305/T306.
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Using a T286D mutation alone is problematic because it generates a constitutively active kinase that then results in phosphorylation of T305/T306, which can counteract T286D and alter resident time at the synapse.
“Just using a T286D mutation would be problematic because it generates a constitutively active kinase that then results in the phosphorylation of T305/T306, which can counteract T286D and alter resident time at the synapse (88, 210, 211).”
From Synaptic memory and CaMKII (2023) · cites this paper as [210]
The Results describe T286D as an active form of CaMKII and hypothesize that it might autophosphorylate T305/T306; they do not establish that this phosphorylation necessarily occurs. The Results and Discussion show that T305/T306 phosphorylation can counteract T286D-associated potentiation, and the Discussion says it reduces binding to the postsynaptic density. The paper does not report a change in residence time at the synapse (page numbers unavailable in our copy). (LLM, conf=0.86)
Experimental — accuracy not yet measuredOverexpressing constitutively active CaMKII promotes plasticity.
“This outcome would be consistent with our results showing enhanced excitatory signaling to D2-MSNs following stress and other results showing overexpression of a constitutively active CaMKII promotes plasticity (89), while developmental inhibition of CaMKII reduces functional numbers of synapses (90).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [89]
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“…Physiol Rev (cid:1) VOL 103 (cid:1) OCTOBER 2023 (cid:1) www.prv.org 2909 T286D mutation would be problematic because it generates a constitutively active kinase that then results in the phosphorylation of T305/T306, which can counter-act T286D and alter resident time at the synapse (88, 210, 211).”
BackgroundSubunit-specific role for the amino-terminal domain of AMPA receptors in synaptic targeting
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- Authors
- Pi, H. J., Otmakhov, N., Lemelin, D., De Koninck, P., & Lisman, J.
- Affiliations
- Brandeis University (US)
- Université Laval (CA)
- Corresponding author
- Lisman, J.
- ORCID
- Lisman, J.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-06-30
- Volume
- 30
- Issue
- 26
- Pages
- 8704-8709
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2903435
- OpenAlex
- W2094501373
- Cited by
- 125
- References
- 40
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 9 · 2017: 10 · 2016: 10 · 2015: 9 · 2014: 14 · 2013: 7 · 2012: 13
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute of Neurological Disorders and Stroke (R01NS050944, R01NS027337)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CaMKII, long-term potentiation, long-term depression, holoenzyme, synaptic plasticity, hippocampal neurons, phosphorylation state, synaptic depression
- MeSH terms
- Amino Acid Sequence, Animals, Hippocampus, Mutation, Neurons, Phosphorylation, Synapses, Time Factors, Transfection, Long-Term Potentiation, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Holoenzymes, Long-Term Synaptic Depression, Calcium-Calmodulin-Dependent Protein Kinase Type 2, In Vitro Techniques
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