DOI: 10.1161/01.res.83.5.560. Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 α Subunit

Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 α Subunit

10.1161/01.res.83.5.560

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Circulation Research (276)

Abstract

Abstract—A novel in vivo experimental strategy, involving cell type–specific expression of a dominant-negative K+channel pore-forming α subunit, was developed and exploited to probe the molecular identity of the cardiac transient outward K+current (Ito). A point mutation (W to F) was introduced at position 362 in the pore region of Kv4.2 to produce a nonconducting mutant (Kv4.2W362F) subunit. Coexpression of Kv4.2W362F with Kv4.2 (or Kv4.3) attenuates the wild-type currents, and the effect is subfamily specific; ie, Kv4.2W362F does not affect heterologously expressed Kv1.4 currents. With the use of the α-myosin heavy chain promoter to direct cardiac-specific expression, several lines of Kv4.2W362F transgenic mice were generated. Electrophysiological recordings reveal thatItois selectively eliminated in ventricular myocytes isolated from transgenic mice expressing Kv4.2W362F, thereby demonstrating directly that the Kv 4 subfamily underliesItoin the mammalian heart. Functional knockout ofItoleads to marked increases in action potential durations in ventricular myocytes and to prolongation of the QT interval in surface ECG recordings. In addition, a novel rapidly activating and inactivating K+current, which is not detectable in myocytes from nontransgenic littermates, is evident in Kv4.2W362F-expressing ventricular cells. Importantly, these results demonstrate that electrical remodeling occurs in the heart when the expression of endogenous K+channels is altered.

Bibliography

Barry, D. M., Xu, H., Schuessler, R. B., & Nerbonne, J. M. (1998). Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 Î± Subunit. Circulation Research, 83(5), 560â567.

Authors 4

Dianne M. Barry (first)
Haodong Xu (additional)
Richard B. Schuessler (additional)
Jeanne M. Nerbonne (additional)

References 34 Referenced 204

10.1146/annurev.ph.58.030196.002051
Campbell DL Rasmusson RL Comer MB Strauss HC. The cardiac calcium-independent transient outward potassium current: kinetics molecular properties and role in ventricular repolarization. In: Zipes DP Jalife J eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia Pa: WB Saunders Co; 1995:83–96.
Kass RS. Delayed potassium channels in the heart: cellular molecular and regulatory properties In: Zipes DP Jalife J eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia Pa: WB Saunders Co; 1995:74–82.
10.1016/S0008-6363(95)00073-9
10.1161/res.79.4.669
10.1161/res.80.6.772
10.1038/ng0196-17
10.1016/0092-8674(95)90358-5
10.1016/0092-8674(95)90340-2
10.1126/science.7604285
10.1038/384078a0
10.1038/384080a0
10.1161/res.75.2.8033339
10.1161/res.77.2.361
10.1161/res.79.4.659
10.1085/jgp.108.5.405
10.1113/jphysiol.1997.sp021998
Sanguinetti MC, Johnson JH, Hammerland LG, Kelbaugh PR, Volkmann RA, Saccomano NA, Mueller AL. Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels. Mol Pharmacol. 1997;51:491–498. (10.1016/S0026-895X(24)13491-8) / Mol Pharmacol (1997)
10.1161/res.72.6.8495559
10.1161/res.75.6.7955154
10.1016/0896-6273(93)90190-3
10.1523/JNEUROSCI.16-03-01123.1996
10.1083/jcb.111.6.2427
10.1161/res.68.6.2036722
10.1126/science.7761854
10.1161/res.78.3.504
10.1172/JCI119367
10.1073/pnas.95.6.2926
10.1016/0896-6273(91)90279-9
10.1161/res.81.1.120
10.1074/jbc.272.42.26505
10.1111/j.1469-7793.1997.557bd.x
10.1016/S0021-9258(19)74340-3
10.1016/0028-3908(96)00095-0

Dates

Type	When
Created	13 years, 2 months ago (June 11, 2012, 8:47 p.m.)
Deposited	4 months, 4 weeks ago (March 30, 2025, 4:55 p.m.)
Indexed	21 hours, 49 minutes ago (Aug. 29, 2025, 5:44 a.m.)
Issued	26 years, 11 months ago (Sept. 7, 1998)
Published	26 years, 11 months ago (Sept. 7, 1998)
Published Print	26 years, 11 months ago (Sept. 7, 1998)

Funders 0

None

BibTeX

@article{Barry_1998, title={Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 α Subunit}, volume={83}, ISSN={1524-4571}, url={http://dx.doi.org/10.1161/01.res.83.5.560}, DOI={10.1161/01.res.83.5.560}, number={5}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Barry, Dianne M. and Xu, Haodong and Schuessler, Richard B. and Nerbonne, Jeanne M.}, year={1998}, month=sep, pages={560–567} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        29
      ]
    ],
    "date-time": "2025-08-29T09:44:29Z",
    "timestamp": 1756460669946,
    "version": "3.40.3"
  },
  "reference-count": 34,
  "publisher": "Ovid Technologies (Wolters Kluwer Health)",
  "issue": "5",
  "content-domain": {
    "domain": [
      "www.ahajournals.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        1998,
        9,
        7
      ]
    ]
  },
  "abstract": "<jats:p><jats:italic>Abstract</jats:italic>\u2014A novel in vivo experimental strategy, involving cell type\u2013specific expression of a dominant-negative K<jats:sup>+</jats:sup>channel pore-forming \u03b1 subunit, was developed and exploited to probe the molecular identity of the cardiac transient outward K<jats:sup>+</jats:sup>current (<jats:italic>I</jats:italic><jats:sub>to</jats:sub>). A point mutation (W to F) was introduced at position 362 in the pore region of Kv4.2 to produce a nonconducting mutant (Kv4.2W362F) subunit. Coexpression of Kv4.2W362F with Kv4.2 (or Kv4.3) attenuates the wild-type currents, and the effect is subfamily specific; ie, Kv4.2W362F does not affect heterologously expressed Kv1.4 currents. With the use of the \u03b1-myosin heavy chain promoter to direct cardiac-specific expression, several lines of Kv4.2W362F transgenic mice were generated. Electrophysiological recordings reveal that<jats:italic>I</jats:italic><jats:sub>to</jats:sub>is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing Kv4.2W362F, thereby demonstrating directly that the Kv 4 subfamily underlies<jats:italic>I</jats:italic><jats:sub>to</jats:sub>in the mammalian heart. Functional knockout of<jats:italic>I</jats:italic><jats:sub>to</jats:sub>leads to marked increases in action potential durations in ventricular myocytes and to prolongation of the QT interval in surface ECG recordings. In addition, a novel rapidly activating and inactivating K<jats:sup>+</jats:sup>current, which is not detectable in myocytes from nontransgenic littermates, is evident in Kv4.2W362F-expressing ventricular cells. Importantly, these results demonstrate that electrical remodeling occurs in the heart when the expression of endogenous K<jats:sup>+</jats:sup>channels is altered.</jats:p>",
  "DOI": "10.1161/01.res.83.5.560",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2012,
        6,
        12
      ]
    ],
    "date-time": "2012-06-12T00:47:05Z",
    "timestamp": 1339462025000
  },
  "page": "560-567",
  "update-policy": "https://doi.org/10.1161/crossmarkpolicy",
  "source": "Crossref",
  "is-referenced-by-count": 204,
  "title": "Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 \u03b1 Subunit",
  "prefix": "10.1161",
  "volume": "83",
  "author": [
    {
      "given": "Dianne M.",
      "family": "Barry",
      "sequence": "first",
      "affiliation": [
        {
          "name": "From the Departments of Molecular Biology and Pharmacology (D.M.B., H.X., J.M.N.) and Surgery (R.B.S.), Washington University Medical School, St Louis, Mo."
        }
      ]
    },
    {
      "given": "Haodong",
      "family": "Xu",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From the Departments of Molecular Biology and Pharmacology (D.M.B., H.X., J.M.N.) and Surgery (R.B.S.), Washington University Medical School, St Louis, Mo."
        }
      ]
    },
    {
      "given": "Richard B.",
      "family": "Schuessler",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From the Departments of Molecular Biology and Pharmacology (D.M.B., H.X., J.M.N.) and Surgery (R.B.S.), Washington University Medical School, St Louis, Mo."
        }
      ]
    },
    {
      "given": "Jeanne M.",
      "family": "Nerbonne",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From the Departments of Molecular Biology and Pharmacology (D.M.B., H.X., J.M.N.) and Surgery (R.B.S.), Washington University Medical School, St Louis, Mo."
        }
      ]
    }
  ],
  "member": "276",
  "reference": [
    {
      "key": "e_1_3_2_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ph.58.030196.002051"
    },
    {
      "key": "e_1_3_2_2_2",
      "unstructured": "Campbell DL Rasmusson RL Comer MB Strauss HC. The cardiac calcium-independent transient outward potassium current: kinetics molecular properties and role in ventricular repolarization. In: Zipes DP Jalife J eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia Pa: WB Saunders Co; 1995:83\u201396."
    },
    {
      "key": "e_1_3_2_3_2",
      "unstructured": "Kass RS. Delayed potassium channels in the heart: cellular molecular and regulatory properties In: Zipes DP Jalife J eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia Pa: WB Saunders Co; 1995:74\u201382."
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0008-6363(95)00073-9"
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.79.4.669"
    },
    {
      "key": "e_1_3_2_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.80.6.772"
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ng0196-17"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(95)90358-5"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(95)90340-2"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.7604285"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/384078a0"
    },
    {
      "key": "e_1_3_2_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/384080a0"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.75.2.8033339"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.77.2.361"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.79.4.659"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1085/jgp.108.5.405"
    },
    {
      "key": "e_1_3_2_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1113/jphysiol.1997.sp021998"
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "crossref",
      "first-page": "491",
      "DOI": "10.1016/S0026-895X(24)13491-8",
      "volume": "51",
      "year": "1997",
      "unstructured": "Sanguinetti MC, Johnson JH, Hammerland LG, Kelbaugh PR, Volkmann RA, Saccomano NA, Mueller AL. Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels. Mol Pharmacol. 1997;51:491\u2013498.",
      "journal-title": "Mol Pharmacol"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.72.6.8495559"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.75.6.7955154"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0896-6273(93)90190-3"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.16-03-01123.1996"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.111.6.2427"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.68.6.2036722"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.7761854"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.78.3.504"
    },
    {
      "key": "e_1_3_2_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1172/JCI119367"
    },
    {
      "key": "e_1_3_2_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.95.6.2926"
    },
    {
      "key": "e_1_3_2_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0896-6273(91)90279-9"
    },
    {
      "key": "e_1_3_2_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.81.1.120"
    },
    {
      "key": "e_1_3_2_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.272.42.26505"
    },
    {
      "key": "e_1_3_2_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1469-7793.1997.557bd.x"
    },
    {
      "key": "e_1_3_2_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)74340-3"
    },
    {
      "key": "e_1_3_2_34_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0028-3908(96)00095-0"
    }
  ],
  "container-title": "Circulation Research",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://www.ahajournals.org/doi/full/10.1161/01.RES.83.5.560",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2025,
        3,
        30
      ]
    ],
    "date-time": "2025-03-30T20:55:10Z",
    "timestamp": 1743368110000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.ahajournals.org/doi/10.1161/01.RES.83.5.560"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1998,
        9,
        7
      ]
    ]
  },
  "references-count": 34,
  "journal-issue": {
    "issue": "5",
    "published-print": {
      "date-parts": [
        [
          1998,
          9,
          7
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1161/01.RES.83.5.560"
  ],
  "URL": "http://dx.doi.org/10.1161/01.RES.83.5.560",
  "relation": {},
  "ISSN": [
    "0009-7330",
    "1524-4571"
  ],
  "subject": [],
  "container-title-short": "Circulation Research",
  "published": {
    "date-parts": [
      [
        1998,
        9,
        7
      ]
    ]
  },
  "assertion": [
    {
      "value": "1998-04-20",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1998-07-17",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1998-09-07",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}