Carvedilol effectively reversed KCNT1 M267T mutation-induced gain-of-function channel properties, inhibited neuronal hyperexcitability, and exhibited antiseizure effects in a mouse model.
Does carvedilol reduce neuronal hyperexcitability and seizures in models of KCNT1 mutation-associated epilepsy?
Carvedilol reverses gain-of-function channel properties and inhibits neuronal hyperexcitability caused by the epilepsy-associated KCNT1 M267T mutation, suggesting it as a potential antiseizure candidate.
BACKGROUND AND PURPOSE: KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures. EXPERIMENTAL APPROACH: Wild-type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two-electrode voltage-clamp recordings. The single-channel properties were investigated using the excised inside-out patches from HEK293T cells. Through in utero electroporation, WT and M267T Slack channels were expressed in the hippocampal CA1 pyramidal neurons in male mice, followed by the examination of the electrical properties using the whole-cell current-clamp technique. The kainic acid-induced epilepsy model in male mice was used to evalute the antiseizure effects of carvedilol. KEY RESULTS: The KCNT1 M267T mutation enhanced Slack channel function by increasing single-channel open probability. Through screening 16 FDA-approved ion channel blockers, we found that carvedilol effectively reversed the mutation-induced gain-of-function channel properties. Notably, the KCNT1 M267T mutation in the mouse hippocampal CA1 pyramidal neurons affected afterhyperpolarization properties and induced neuronal hyperexcitability, which was inhibited by carvedilol. Additionally, carvedilol exhibited antiseizure effects in the kainic acid-induced epilepsy model. CONCLUSION AND IMPLICATION: Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies.
Chang et al. (Sun,) conducted a other in Epilepsy associated with KCNT1 mutations. Carvedilol was evaluated on Reversal of mutation-induced gain-of-function channel properties and inhibition of neuronal hyperexcitability. Carvedilol effectively reversed KCNT1 M267T mutation-induced gain-of-function channel properties, inhibited neuronal hyperexcitability, and exhibited antiseizure effects in a mouse model.