Familial neonatal seizures caused by the Kv7.3 selectivity filter mutation T313I

Abstract

Objective A spectrum of seizure disorders is linked to mutations in Kv7.2 and Kv7.3 channels. Linking functional effects of identified mutations to their clinical presentation requires ongoing characterization of newly identified variants. In this study, we identified and functionally characterized a previously unreported mutation in the selectivity filter of Kv7.3. Methods Next‐generation sequencing was used to identify the Kv7.3[T313I] mutation in a family affected by neonatal seizures. Electrophysiological approaches were used to characterize the functional effects of this mutation on ion channels expressed in Xenopus laevis oocytes. Results Substitution of residue 313 from threonine to isoleucine (Kv7.3[T313I]) likely disrupts a critical intersubunit hydrogen bond. Characterization of the mutation in homomeric Kv7.3 channels demonstrated a total loss of channel function. Assembly in heteromeric channels (with Kv7.2) leads to modest suppression of total current when expressed in Xenopus laevis oocytes. Using a Kv7 activator with distinct effects on homomeric Kv7.2 vs heteromeric Kv7.2/Kv7.3 channels, we demonstrated that assembly of Kv7.2 and Kv7.3[T313I] generates functional channels. Significance Biophysical and clinical effects of the T313I mutation are consistent with Kv7.3 mutations previously identified in cases of pharmacoresponsive self‐limiting neonatal epilepsy. These findings expand our description of functionally characterized Kv7 channel variants and report new methods to distinguish molecular mechanisms of channel mutations.

Ca2+-sensing receptor regulates neuronal excitability via Kv7 channel and Gi/oprotein signalling

“…However, the well-established interplay between the CaSR and pro-inflammatory cytokines (Iamartino & Brandi, 2022) and the significance of the inflammatory process underlying many neuropathic pain conditions (Ellis & Bennett, 2013;Li et al, 2023) suggests the CaSR as a potential candidate for neuropathic pain therapy. Moreover, based on the evidence that neuronal hyperexcitability is associated with dysfunctions of the CaSR (Kapoor et al, 2008) and neuronal Kv7.2/7.3 channels (Chokvithaya et al, 2023;Maghera et al, 2020;Schroeder et al, 1998), it is conceivable that a crosslink between the CaSR and Kv7.2/7.3 channels may exist and contribute to the regulation of neuronal excitability. This study aimed to establish the molecular pathway linking the CaSR and Kv7.2/7.3 channels, and explore the potential of calcilytics in suppressing neuronal hyperexcitability using a human induced pluripotent stem cell (hiPSC)-derived nociceptive-like neuronal model.…”