Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons

Helen M. Brew, Joshua X. Gittelman, Robert S. Silverstein, Timothy Hanks, Vas P. Demas, Linda C. Robinson, Carol A. Robbins, Jennifer McKee-Johnson, Yan Chiu Shing, Albee Messing, Bruce L. Tempel

Research output: Contribution to journalArticle

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Abstract

Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage-activated potassium current IKv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced IKv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (-/-). The -/- mice exhibited increased seizure susceptibility compared with their +/+ and +/-littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from -/- and +/-mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped -/- MNTB neurons had enlarged IKv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/- Kv1 channels, and no -/- Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger IKv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.

Original languageEnglish (US)
Pages (from-to)1501-1525
Number of pages25
JournalJournal of Neurophysiology
Volume98
Issue number3
DOIs
StatePublished - Sep 2007
Externally publishedYes

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Kv1.2 Potassium Channel
Seizures
Neurons
Brain Stem
Kv1.1 Potassium Channel
Axons
Phenotype
Trapezoid Body
Potassium
Messenger RNA

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology
  • Medicine(all)

Cite this

Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. / Brew, Helen M.; Gittelman, Joshua X.; Silverstein, Robert S.; Hanks, Timothy; Demas, Vas P.; Robinson, Linda C.; Robbins, Carol A.; McKee-Johnson, Jennifer; Shing, Yan Chiu; Messing, Albee; Tempel, Bruce L.

In: Journal of Neurophysiology, Vol. 98, No. 3, 09.2007, p. 1501-1525.

Research output: Contribution to journalArticle

Brew, HM, Gittelman, JX, Silverstein, RS, Hanks, T, Demas, VP, Robinson, LC, Robbins, CA, McKee-Johnson, J, Shing, YC, Messing, A & Tempel, BL 2007, 'Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons', Journal of Neurophysiology, vol. 98, no. 3, pp. 1501-1525. https://doi.org/10.1152/jn.00640.2006
Brew, Helen M. ; Gittelman, Joshua X. ; Silverstein, Robert S. ; Hanks, Timothy ; Demas, Vas P. ; Robinson, Linda C. ; Robbins, Carol A. ; McKee-Johnson, Jennifer ; Shing, Yan Chiu ; Messing, Albee ; Tempel, Bruce L. / Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. In: Journal of Neurophysiology. 2007 ; Vol. 98, No. 3. pp. 1501-1525.
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abstract = "Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage-activated potassium current IKv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced IKv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (-/-). The -/- mice exhibited increased seizure susceptibility compared with their +/+ and +/-littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from -/- and +/-mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped -/- MNTB neurons had enlarged IKv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60{\%} of +/- Kv1 channels, and no -/- Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger IKv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.",
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T1 - Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons

AU - Brew, Helen M.

AU - Gittelman, Joshua X.

AU - Silverstein, Robert S.

AU - Hanks, Timothy

AU - Demas, Vas P.

AU - Robinson, Linda C.

AU - Robbins, Carol A.

AU - McKee-Johnson, Jennifer

AU - Shing, Yan Chiu

AU - Messing, Albee

AU - Tempel, Bruce L.

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AB - Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage-activated potassium current IKv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced IKv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (-/-). The -/- mice exhibited increased seizure susceptibility compared with their +/+ and +/-littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from -/- and +/-mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped -/- MNTB neurons had enlarged IKv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/- Kv1 channels, and no -/- Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger IKv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.

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