Pathogenic gating pore current conducted by autism-related mutations in the NaV1.2 brain sodium channel

• 成果类型: Article
• 署名作者: Eltokhi, Ahmed; Lundstrom, Brian Nils; Li, Jin; Zweifel, Larry S.; Catterall, William A.; El-Din, Tamer M. Gamal
• 署名单位: University of Washington; University of Washington Seattle; Mayo Clinic; University of Washington; University of Washington Seattle; Mercer University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13275
• DOI: 10.1073/pnas.2317769121
• 发表日期: 2024-04-09
• 关键词: hypokalemic periodic paralysis; action-potential initiation; voltage sensor; cerebrospinal-fluid; slow inactivation; spectrum disorder; ion permeation; MOVEMENT; s4; expression

摘要

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ/K(V)7 potassium channel cause gating pore currents (I-gp) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A/Na(V)1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na(V)1.2 caused I-gp in the resting state of similar to 0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I-gp. These potentially pathogenic I-gp were exacerbated by the absence of the extracellular Mg2+ and Ca2+. In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I-gp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.