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1 Otolaryngology-HNS, Univ. of Washington, Seattle, Washington, United States; V.M.Bloedel Hearing Research Center, Univ. of Washington, CD176, CHDD Building, Seattle, Washington, 98115-7923, United States
2 Neurobiology and Behavior, University of Washington, Seattle, Washington, United States; V.M.Bloedel Hearing Research Center, Univ. of Washington, CD176, CHDD Building, Seattle, Washington, 98115-7923, United States
3 V.M.Bloedel Hearing Research Center, Univ. of Washington, CD176, CHDD Building, Seattle, Washington, 98115-7923, United States; Neurobiology and Behavior, University of Washington, Seattle, Washington, United States
4 Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington, United States
5 V.M.Bloedel Hearing Research Center, Univ. of Washington, CD176, CHDD Building, Seattle, Washington, 98115-7923, United States
6 University of Washington, United States; V.M.Bloedel Hearing Research Center, Univ. of Washington, CD176, CHDD Building, Seattle, Washington, 98115-7923, United States
7 Neurological Surgery, University of Washington, Seattle, Washington, United States
8 Physiology, University of Wisconsin, Madison, Wisconsin, United States
9 Waisman Center, University of Wisconsin, Madison, Wisconsin, United States
10 Bloedel Hearing Research Center, University of Washington, Seattle, Washington, United States
* To whom correspondence should be addressed. E-mail: hbrew{at}u.washington.edu.
Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2 which are co-expressed 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 to their +/+ and +/- littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brainstems between P7 and P14, suggesting these subunits increasing importance for limiting excitability. Surprisingly, MNTB neurons in brainstem 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, approximately 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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  E. C. Connors, B. A. Ballif, and A. D. Morielli Homeostatic Regulation of Kv1.2 Potassium Channel Trafficking by Cyclic AMP J. Biol. Chem., February 8, 2008; 283(6): 3445 - 3453. [Abstract] [Full Text] [PDF]
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 J.-W. Yang, H. Vacher, K.-S. Park, E. Clark, and J. S. Trimmer Trafficking-dependent phosphorylation of Kv1.2 regulates voltage-gated potassium channel cell surface expression PNAS, December 11, 2007; 104(50): 20055 - 20060. [Abstract] [Full Text] [PDF]
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