DOI: 10.1073/pnas.1932759100. An ultrasensitive Ca <sup>2+</sup> /calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling

An ultrasensitive Ca 2+ /calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling

10.1073/pnas.1932759100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The strength of hippocampal synapses can be persistently increased by signals that activate Ca 2+ /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 Ca 2+ concentration [Hill coefficient (n H ) ≈ 5]. However, an even steeper Ca 2+ dependence (n H ≈ 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 Ca 2+ 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 Ca 2+ signals into all-or-none potentiation of individual hippocampal synapses.

Bibliography

Bradshaw, J. M., Kubota, Y., Meyer, T., & Schulman, H. (2003). An ultrasensitive Ca 2+ /calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling. Proceedings of the National Academy of Sciences, 100(18), 10512â10517.

Authors 4

J. Michael Bradshaw (first)
Yoshi Kubota (additional)
Tobias Meyer (additional)
Howard Schulman (additional)

References 32 Referenced 162

Dates

Type	When
Created	21 years, 11 months ago (Sept. 2, 2003, 1:27 p.m.)
Deposited	3 years, 4 months ago (April 25, 2022, 9:27 p.m.)
Indexed	1 month ago (July 28, 2025, 2:24 a.m.)
Issued	22 years ago (Aug. 19, 2003)
Published	22 years ago (Aug. 19, 2003)
Published Online	22 years ago (Aug. 19, 2003)
Published Print	21 years, 11 months ago (Sept. 2, 2003)

Funders 0

None

BibTeX

@article{Bradshaw_2003, title={An ultrasensitive Ca 2+ /calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1932759100}, DOI={10.1073/pnas.1932759100}, number={18}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Bradshaw, J. Michael and Kubota, Yoshi and Meyer, Tobias and Schulman, Howard}, year={2003}, month=aug, pages={10512–10517} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        28
      ]
    ],
    "date-time": "2025-07-28T06:24:24Z",
    "timestamp": 1753683864625
  },
  "reference-count": 32,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "18",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2003,
        9,
        2
      ]
    ]
  },
  "abstract": "<jats:p>\n            The strength of hippocampal synapses can be persistently increased by\n signals that activate Ca\n            <jats:sup>2+</jats:sup>\n            /calmodulin-dependent protein kinase II\n (CaMKII). This CaMKII-dependent long-term potentiation is important for\n hippocampal learning and memory. In this work we show that CaMKII exhibits an\n intriguing switch-like activation that likely is important for changes in\n synaptic strength. We found that autophosphorylation of CaMKII by itself\n showed a steep dependence on Ca\n            <jats:sup>2+</jats:sup>\n            concentration [Hill coefficient\n (n\n            <jats:sub>H</jats:sub>\n            ) \u2248 5]. However, an even steeper Ca\n            <jats:sup>2+</jats:sup>\n            dependence\n (n\n            <jats:sub>H</jats:sub>\n            \u2248 8) was observed when autophosphorylation is balanced by\n the dephosphorylation activity of protein phosphatase 1 (PP1). This\n autophosphorylation-dephosphorylation switch was found to be reversible\n because PP1 dephosphorylates CaMKII when Ca\n            <jats:sup>2+</jats:sup>\n            is lowered to a basal\n level. The switch-like response of a CaMKII-PP1 system suggests that CaMKII\n and PP1 may function together as a simple molecular device that specifically\n translates only strong Ca\n            <jats:sup>2+</jats:sup>\n            signals into all-or-none potentiation\n of individual hippocampal synapses.\n          </jats:p>",
  "DOI": "10.1073/pnas.1932759100",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2003,
        9,
        2
      ]
    ],
    "date-time": "2003-09-02T17:27:00Z",
    "timestamp": 1062523620000
  },
  "page": "10512-10517",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 162,
  "title": "An ultrasensitive Ca\n            <sup>2+</sup>\n            /calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling",
  "prefix": "10.1073",
  "volume": "100",
  "author": [
    {
      "given": "J. Michael",
      "family": "Bradshaw",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Departments of Neurobiology and\r Molecular Pharmacology, Stanford University\r School of Medicine, Stanford, CA 94305"
        }
      ]
    },
    {
      "given": "Yoshi",
      "family": "Kubota",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Neurobiology and\r Molecular Pharmacology, Stanford University\r School of Medicine, Stanford, CA 94305"
        }
      ]
    },
    {
      "given": "Tobias",
      "family": "Meyer",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Neurobiology and\r Molecular Pharmacology, Stanford University\r School of Medicine, Stanford, CA 94305"
        }
      ]
    },
    {
      "given": "Howard",
      "family": "Schulman",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Neurobiology and\r Molecular Pharmacology, Stanford University\r School of Medicine, Stanford, CA 94305"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2003,
        8,
        19
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_2_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1075333"
    },
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/bies.10193"
    },
    {
      "key": "e_1_3_2_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0896-6273(02)00573-1"
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/bies.10057"
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nrn753"
    },
    {
      "key": "e_1_3_2_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0959-4388(02)00327-6"
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.biochem.71.110601.135410"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.R000013200"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.276.5321.2042"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.284.5411.162"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.100.3.835"
    },
    {
      "key": "e_1_3_2_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.279.5352.870"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/369486a0"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1017/S0033583500003449"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0968-0004(96)20026-X"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0896-6273(01)00364-6"
    },
    {
      "key": "e_1_3_2_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M202154200"
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M101744200"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.051003898"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0091-679X(08)61108-5"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1023/A:1013727331979"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)98996-9"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.279.5348.227"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0896-6273(94)90306-9"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0968-0004(98)01316-4"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0006-3495(00)76469-1"
    },
    {
      "key": "e_1_3_2_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/PL00007960"
    },
    {
      "key": "e_1_3_2_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.94.8.3530"
    },
    {
      "key": "e_1_3_2_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.86.23.9574"
    },
    {
      "key": "e_1_3_2_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.95.8.4732"
    },
    {
      "key": "e_1_3_2_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35081080"
    },
    {
      "key": "e_1_3_2_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.280.5371.1940"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.1932759100",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        26
      ]
    ],
    "date-time": "2022-04-26T01:27:46Z",
    "timestamp": 1650936466000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.1932759100"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2003,
        8,
        19
      ]
    ]
  },
  "references-count": 32,
  "journal-issue": {
    "issue": "18",
    "published-print": {
      "date-parts": [
        [
          2003,
          9,
          2
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.1932759100"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.1932759100",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2003,
        8,
        19
      ]
    ]
  },
  "assertion": [
    {
      "value": "2003-05-07",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2003-08-19",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}