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Cited by 292Protein Kinase Regulation and GTPase SignalingSignaling Pathways in DiseaseNeuroscience and Neuropharmacology Research

Autophosphorylation reversibly regulates the Ca2+/calmodulin-dependence of Ca2+/calmodulin-dependent protein kinase II.

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Lai, Y, Nairn, A C, Greengard, P·1986·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.83.12.4253PMC PMC323710
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Abstract

Ca2+/calmodulin-dependent protein kinase II contains two subunits, alpha (Mr 50,000) and beta (Mr 60,000/58,000), both of which undergo Ca2+/calmodulin-dependent autophosphorylation. In the present study, we have studied the mechanism of this autophosphorylation reaction and its effect on the activity of the enzyme. Both subunits are autophosphorylated through an intramolecular mechanism. Using synapsin I as substrate, Ca2+/calmodulin-dependent protein kinase II, in its unphosphorylated form, was totally dependent on Ca2+ and calmodulin for its activity. Preincubation of the enzyme with Ca2+, calmodulin, and ATP, under conditions where autophosphorylation of both subunits occurred, converted the enzyme to one that was only partially dependent on Ca2+ and calmodulin for its activity. No change in the total activity, measured in the presence of Ca2+ and calmodulin, was observed. The nonhydrolyzable ATP analog adenosine 5'-[beta, gamma-imido] triphosphate did not substitute for ATP in the preincubation. Moreover, dephosphorylation of autophosphorylated Ca2+/calmodulin-dependent protein kinase II with protein phosphatase 2A resulted in an enzyme that was again totally dependent on Ca2+ and calmodulin for its activity. We propose that autophosphorylation and dephosphorylation reversibly regulate the Ca2+ and calmodulin requirement of Ca2+/calmodulin-dependent protein kinase II.

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  • 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 [13]

  • 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 [13]

  • 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 [13]

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Authors
Lai, Y., Nairn, A. C., & Greengard, P.
Affiliations
Rockefeller University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1986-06
Volume
83
Issue
12
Pages
4253-4257
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.83.12.4253
PMC
PMC323710
OpenAlex
W2011962611
Cited by
292
References
33
Citations by year
2026: 1 · 2025: 5 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 5 · 2012: 6
FWCI
10.93
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
calcium/calmodulin-dependent protein kinase II, autophosphorylation, kinase regulation, synapsin I, protein phosphatase 2A, dephosphorylation, ATP requirement, enzyme activation
MeSH terms
Adenosine Triphosphate, Animals, Calcium, Calmodulin, Enzyme Activation, Hot Temperature, Kinetics, Phosphoprotein Phosphatases, Phosphorylation, Protein Kinases, Structure-Activity Relationship, Rats, Protein Phosphatase 2

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