Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression

Mulkey, Rosel M.; Endo, Shogo; Shenolikar, Shirish; Malenka, Robert C.

doi:10.1038/369486a0

Cited by 1,083Neuroscience and Neuropharmacology ResearchSignaling Pathways in DiseaseMemory and Neural Mechanisms

Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression

Mulkey, Rosel M., Endo, Shogo, Shenolikar, Shirish, Malenka, Robert C.·1994·Nature

DOI 10.1038/369486a0

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Abstract

Long-term potentiation (LTP) is a synaptic mechanism thought to be involved in learning and memory. Long-term depression (LTD), an activity-dependent decrease in synaptic efficacy, may be an equally important mechanism which permits neural networks to store information more effectively. One form of LTD that has been observed in the hippocampus requires activation of postsynaptic NMDA (N-methyl-D-aspartate) receptors, a change in postsynaptic calcium concentration, and activation of postsynaptic serine/threonine protein phosphatase 1 (PP1) or 2A (PP2A). The mechanism by which PP1 or PP2A is regulated by synaptic activity is unclear because these protein phosphatases are not directly influenced by calcium concentration. LTD induction may require activation of a more complex protein phosphatase cascade consisting of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, its phosphoprotein substrate, inhibitor-1, and PP1. We tested this hypothesis using calcineurin inhibitors as well as different forms of inhibitor-1 loaded into postsynaptic cells. Our results suggest a signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor-1. This in turn increases PP1 activity and contributes to the generation of LTD.

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LTD is induced by the activation of a high-affinity Ca2+ cascade resulting in the activation of PP1.
“In a series of classic studies it was found that LTD is induced by the activation of a high-affinity Ca2+ cascade resulting in the activation of PP1 (395–397).”
From Synaptic memory and CaMKII (2023) · cites this paper as [397]

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Authors: Mulkey, R. M., Endo, S., Shenolikar, S., & Malenka, R. C.
Affiliations: University of California, San Francisco (US)
Duke Medical Center (US)
ORCID: Endo, Shogo
Shenolikar, Shirish
Malenka, Robert C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1994-06
Volume: 369
Issue: 6480
Pages: 486-488
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/369486a0
OpenAlex: W2017842551
Cited by: 1,083
References: 0
Citations by year: 2026: 18 · 2025: 13 · 2024: 18 · 2023: 17 · 2022: 15 · 2021: 29 · 2020: 24 · 2019: 27 · 2018: 30 · 2017: 28 · 2016: 31 · 2015: 26 · 2014: 29 · 2013: 46 · 2012: 38
FWCI: 16.12
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords: long-term depression, calcineurin, protein phosphatase 1, protein phosphatase 2A, hippocampus, NMDA receptor, dephosphorylation, synaptic plasticity
MeSH terms: Animals, Calmodulin-Binding Proteins, Carrier Proteins, Hippocampus, Phosphoprotein Phosphatases, Phosphorylation, Proteins, Synapses, Tacrolimus, Cyclosporine, Rats, Sprague-Dawley, Calcineurin, Intracellular Signaling Peptides and Proteins, Rats, Protein Phosphatase 1, In Vitro Techniques

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Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression

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