Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons.
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.
Brew
Helen M
HM
Virginia Merrill Bloedel Hearing Research Center, Box 357923, University of Washington, Seattle, WA 98195-7923, USA.
Gittelman
Joshua X
JX
Silverstein
Robert S
RS
Hanks
Timothy D
TD
Demas
Vas P
VP
Robinson
Linda C
LC
Robbins
Carol A
CA
McKee-Johnson
Jennifer
J
Chiu
Shing Yan
SY
Messing
Albee
A
Tempel
Bruce L
BL
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*
D051663:Kv1.2 Potassium Channel; D051637:Shaker Superfamily of Potassium Channels