title: Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons.
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 I Kv1, 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 I Kv1. 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 I Kv1. 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 I Kv1. 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.
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Box 357923, University of Washington, Seattle, WA 98195-7923, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Brew
authors.forename: Joshua X
authors.initials: JX
authors.lastname: Gittelman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Silverstein
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Hanks
authors.forename: Vas P
authors.initials: VP
authors.lastname: Demas
authors.forename: Linda C
authors.initials: LC
authors.lastname: Robinson
authors.forename: Carol A
authors.initials: CA
authors.lastname: Robbins
authors.forename: Jennifer
authors.initials: J
authors.lastname: McKee-Johnson
authors.forename: Shing Yan
authors.initials: SY
authors.lastname: Chiu
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Tempel
mesh_terms: D000375:Aging; D000818:Animals; D001933:Brain Stem / Q000502:physiology / Q000503:physiopathology; D005822:Genetic Vectors; D016678:Genome; D005838:Genotype; D051663:Kv1.2 Potassium Channel / Q000172:deficiency* / Q000502:physiology*; D008017:Life Expectancy; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D016366:Open Reading Frames; D015183:Restriction Mapping; D012640:Seizures / Q000235:genetics*; D051637:Shaker Superfamily of Potassium Channels / Q000502:physiology*
chemical_list: D051663:Kv1.2 Potassium Channel; D051637:Shaker Superfamily of Potassium Channels