Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

Abstract

Voltage-gated sodium (Nav) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Cav) channel Cav1.1 provides a template for homology-based structural modeling of the evolutionarily related Nav channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nav1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nav channels, the analysis presented here serves as the base framework for mechanistic investigation of Nav channelopathies and for potential structure-based drug discovery.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-017-0372-z) contains supplementary material, which is available to authorized users.

Chemical modification of proteins by insertion of synthetic peptides using tandem protein trans-splicing

“…To further validate our approach and demonstrate its suitability for other target sequences, we applied the same strategy to the intracellular linker connecting DI and II of NaV1.5. Similar to the DIII-IV linker, mutations or aberrant PTMs in this region of NaV1.5 have been implicated in cardiac disease 23,29 . Using appropriate N and C constructs, together with both recombinantly expressed and synthetic versions of a peptide XNav1.5 variant corresponding to amino acids 505 to 527 of NaV1.5, we demonstrated that tPTS can be used to probe the function of different intracellular regions of NaV1.5 in Xenopus oocytes.…”

Sodium Channelopathies of Skeletal Muscle

“…The inheritance pattern is autosomal dominant and highly penetrant, except for the very rare syndrome of congenital myopathy which is autosomal recessive. Over 70 mutations of SCN4A have been identified in patients with skeletal muscle disorders (Huang et al, 2017; Lehmann-Horn and Jurkat-Rott, 1999). Genotype-phenotype associations have emerged (Miller et al, 2004; Rüdel et al, 1993), wherein specific mutations are consistently found to cause a particular clinical syndrome amongst the 6 allelic disorders of the muscle sodium channelopathies (Fig.…”

Backbone resonance assignments of complexes of apo human calmodulin bound to IQ motif peptides of voltage-dependent sodium channels NaV1.1, NaV1.4 and NaV1.7

“…Na V channelopathies lead to serious diseases affecting nervous system function, heart rhythm, and skeletal muscle contraction (see review in (Huang et al 2017)). Pathologies of isoforms expressed in the CNS include Na V 1.1 defects that are associated with Dravet syndrome, severe epilepsy, sleep disturbance, and cognitive impairment.…”