Episodic ataxia type 1 (EA1) is an autosomal dominant human disorder which produces attacks of generalized ataxia as well as cognitive dysfunction. One familial form of EA1 is believed to result from abnormalities in the excitability of central and peripheral nerves. Genetic linkage studies have proven that this form of EA1 is due to mutations in the gene encoding the voltage-dependent delayed rectifier potassium channel Kv1.1. To date, each of nine EA1 families examined have members which are heterozygous at the Kv1.1 locus, harboring one normal allele and one allele containing a single missense mutation in the Kv1.1 coding sequence; each family harbors a distinct mutation, and every heterozygote is affected. Heterologous expression of six of these EA1 subunits in Xenopus oocytes demonstrates that five alleles produce homomeric channels which are functionally distinct from wild type channels while one of them produces nonfunctional homomeric channels. Coexpression with wild type subunits shows that EA1 subunits alter potassium channel function either by haplotype insufficiency, too few subunits, or by dominant negative effects, interfering with wild type channels presumable through coassembly. We hypothesize that the clinical symptoms of EA1 result from altered Kv1.1 function leading to action potential prolongation in affected central nerve cells. In the cerebellum, Kv1.1 is primarily localized with GABA in the axon terminals of the plexus region of basket cells and interneurons of the granule cell layer. The co-localization with GABA suggests a functional role for Kv1.1 in the control of GABA release and we postulate that the attacks of ataxia result from a prolonged release of GABA in the cerebellum. To understand the molecular physiology of EA1, we first propose detailed functional analyses of EA1 subunits and their interaction with wild type Kv1.1, Kv1.2, ^D1 and ^D2 subunits using COS7 cells and the Xenopus oocyte expression system. Whole cell and single channel recording and sub-cellular localization will elucidate the molecular mechanisms through which EA1 subunits alter potassium channel function. To determine how altered potassium channel function leads to the symptoms of EA1 we propose the construction of two transgenic mice strains, each harboring a distinct EA1 allele. These mice will be used for the characterization of motor function and the electrophysiological and pharmacological properties of GABAergic cells in the cerebellum. These studies will provide a detailed understanding of EA1 and that may lead to new treatments. They will also provide new information regarding the involvement of a particular molecular species of ion channel in the complexity of motor control.
| Luján, Rafael; Maylie, James; Adelman, John P (2009) New sites of action for GIRK and SK channels. Nat Rev Neurosci 10:475-80 |
