Oral Presentation 2014 International Biophysics Congress

Altered gating of voltage-dependent K+ channels in early-onset neurological diseases (#202)

Diane M. Papazian 1
  1. Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Kv3 and Kv4 K+ channels have specialized gating properties that confer on neurons distinct patterns of action potential firing. Kv3 channels activate in a depolarized voltage range with fast activation and deactivation kinetics, and promote sustained, high frequency firing. Kv4 channels activate at sub-threshold voltages and inactivate from pre-open and open states via uncoupling of the voltage sensor and pore gate. Inactivation controls the availability of Kv4-containing channels, which delay the first spike in a train, reduce the frequency of repetitive firing, and prevent back propagation of action potentials into dendrites. Altering the specialized gating properties of Kv3 or Kv4 channels results in severe infant-onset diseases. Kv3.3 mutations cause spinocerebellar ataxia type 13 (SCA13), which exists in two clinical forms that differ in the age of onset. Infant-onset SCA13 is characterized by severe cerebellar atrophy early in life, persistent motor problems, and intellectual disability. We found that Kv3.3 mutations that cause infant-onset SCA13 dominantly alter activation gating with or without reducing current amplitude. In contrast, in adult-onset SCA13, the mutant subunit reduces current amplitude but the residual current is functionally normal. Recently, a de novo Kv4.2 mutation, V404M, was identified by exome sequencing in identical twins with intractable seizures in infancy and autism. This mutation significantly impairs Kv4 inactivation in a state-dependent manner, with a more severe effect on inactivation after opening than from pre-open closed states. Thus, SCA13 mutations in Kv3.3 and V404M in Kv4.2 specifically alter novel gating properties that are responsible for the specialized roles of these channels in controlling neuronal excitability, resulting in early-onset neurological diseases. We are using zebrafish, a lower vertebrate, to investigate the in vivo consequences of these mutations, characterize their effects on neuronal excitability, and identify downstream effectors that could underlie pathogenesis in SCA13 and in epilepsy coupled with autism.