Abstract
One of the major factors known to cause neuronal hyperexcitability is malfunction of the potassium ion channels underlying the M-current -formed by KCNQ2 and KCNQ3-. The slow kinetics of activation and deactivation of KCNQ2/KCNQ3 channel ensures that the M-current regulates the membrane potential and impede repetitive neuronal firing. Inherited mutations in KCNQ2 and KCNQ3 channels are linked with a wide spectrum of early-onset epileptic disorders ranging from benign familial neonatal seizures to severe epileptic encephalopathies. Here, we investigate the molecular mechanisms by which epilepsy-associated mutations in the voltage sensor (S4) of KCNQ2/KCNQ3 cause channel malfunction. Because polyunsaturated fatty acids (PUFAs) have been shown to alleviate the symptoms of intractable epileptic seizures, we also investigate the mechanisms by which these compounds reverse channel malfunction and therefore improve neuronal function. We use voltage clamp fluorometry (VCF), to measure simultaneously voltage sensor movement and gate opening during channel activation in these mutations. We show that that epilepsy-causing mutations in KCNQ channels affect voltage sensor movement and that PUFA variants can restore normal voltage dependence of voltage sensor movement in mutated KCNQ channels. Using optogenetic, we also show that PUFA variants reduce activity in iPSC-derived cortical neurons bearing epilepsy-associated mutations in KCNQ channels. Our results suggest that, compounds that left-shift the voltage dependence of S4 activation in loss-of-function mutations would promote gate opening and have therapeutic potential.
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