Overview
KCNMA1-N999S knock-in mice express a gain-of-function (GOF) asparagine to serine substitution at position 999 of the potassium large conductance calcium-activated channel, subfamily M, alpha member 1 gene. Mice exhibit increased channel activity, decreased seizure thresholds, and become immobile following (stress) restraint. These mice may be useful as a model for paroxysmal nonkinesigenic dyskinesia (PNKD3) with increased seizure propensity.
KCNMA1 (potassium large conductance calcium-activated channel, subfamily M, alpha member 1) encodes the pore-forming alpha subunit of the "Big K+" (BK) voltage and calcium-sensitive potassium channel (KCa1.1). BK channels regulate membrane potential and repolarization of action potentials and are widely expressed in neurons, smooth muscle, neuroendocrine and non-excitable cells such as bone and kidney. In excitable cells, BK channels regulate action potential repolarizations and afterhyperpolarizations, neurotransmitter release, and calcium transients. Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability, specifically paroxysmal non-kinesigenic dyskinesia (PKND3) with or without epileptic seizures.
KCNMA1-N999S knock-in mice express gain-of-function (GOF) asparagine to serine substitution at position 999 (N999S; rs886039469). The heterozygous N999S mutation is the most common de novo KCNMA1 variant found in patients (17%), half of which develop seizures, paroxysmal non-kinesigenic dyskinesia (PKND3), or both. N999S is located in the helix bend in the middle of the S10 domain within the regulator of conductance of potassium 2 (RCK2) domain. Mice heterozygous for the mutation are viable and fertile with no apparent abnormalities. Heterozygote x heterozygote crosses do not produce homozygous progeny. KCNMA1-N999S mice exhibit lowered seizure thresholds, locomotor dysfunction, hypokinetic stress-induced paroxysmal dyskinesia (episodes of immobility),and increased BK channel activity (increased currents [69%] and action potential firing [25-30%]). In addition, severely affected KCNMA1-N999S/WT mice become immobile (hypokinetic) for 101+/-11 seconds as compared to wildtype (63+/-6 seconds after stress restraint, a trigger for paroxysmal dyskinesia. The stress-induced paroxysmal dyskinesia exhibited by KCNMA1-N999S mice is mitigated by acute dextroamphetamine treatment, consistent with the amphetamine responsiveness of PNKD3-affected patients harboring the N999S variant.
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