Abstract
Kv1.1 belongs to the Shaker subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. KCNA1 is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal dominant disorder characterized by ataxia and myokymia and for which different and variable phenotypes have now been reported. The iterative characterization of channel defects at the molecular, network, and organismal levels contributed to elucidating the functional consequences of KCNA1 mutations and to demonstrate that ataxic attacks and neuromyotonia result from cerebellum and motor nerve alterations. Dysfunctions of the Kv1.1 channel have been also associated with epilepsy and kcna1 knock-out mouse is considered a model of sudden unexpected death in epilepsy. The tissue-specific association of Kv1.1 with other Kv1 members, auxiliary and interacting subunits amplifies Kv1.1 physiological roles and expands the pathogenesis of Kv1.1-associated diseases. In line with the current knowledge, Kv1.1 has been proposed as a novel and promising target for the treatment of brain disorders characterized by hyperexcitability, in the attempt to overcome limited response and side effects of available therapies. This review recounts past and current studies clarifying the roles of Kv1.1 in and beyond the nervous system and its contribution to EA1 and seizure susceptibility as well as its wide pharmacological potential.
Highlights
The S4 movement is conveyed, through the S4–S5 linker, to the S5–S6 pore to drive the opening and closing of the channel [1]
The repurposing of riluzole, is suggested as a treatment for epilepsy caused by LGI1, KCNA1 or KCNA2 mutations [129]
We have illustrated the different aspects of Kv1.1 channels dysfunctions underlying distinct episodic ataxia type 1 (EA1), epileptic and cardiac phenotypes in humans and animal models and reported the clinical challenges and recent progress in developing appropriate therapeutic approaches for these diseases
Summary
Kv1.1E283K channels expressed in HEK 293 cells (panels A and B, respectively). Kv1.1E283K channels activate more slowly than Kv1.1WT channels (τ at V1/2 is 5.2 ± 0.2 ms and 11.7 ± 0.6 ms, for WT and E283K channels, respectively), and produce smaller currents. (C) The current-voltage relationships for Kv1.1WT and Kv1.1E283K channels were obtained by plotting the normalized peak tail currents measured at −50 mV as a function of the pre-pulse potentials and fitting data points with a Boltzmann function (V1/2 is −25.8 ± 0.4 mV and −16.5 ± 0.3 mV, for WT and E283K channels, respectively; slope factor is 7.4 ± 0.4 mV and 7.8 ± 0.2 mV, for WT and E283K channels, respectively. (D) Homology model of the mutant Kv1.1E283K, built upon the Kv1.2 crystal structure (PDB code: 3LUT), showing the localization of the E283K mutation (red dots). The EA1 mutation F184C sensitizes both homomeric Kv1.1 and heteromeric Kv1.1/Kv1.4 channel to extracellular Zn2+ block implying that the Zn2+ effects may be additional to the intrinsic gating defect caused by the mutation [33,78,83] These in vitro findings suggest that similar functional alterations may occur in the brain of EA1 patients where Kv1.1, Kv1.2 and Kv1.4 subunits likely co-assemble and Zn2+ is released, recapitulating different clinical phenotypes. Large variability of symptoms has been reported in affected patients and no clear correlation between genotype, functional consequences of single mutations, attack frequency, disease severity, and drug response, even within the same family could be established [52]. Clinical Symptoms Severe stiffness, muscle cramps, pain Ataxia, dysarthria, neuromyotonia
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