Selenomethionine mis‐incorporation and redox‐dependent voltage‐gated sodium channel gain of function

Abstract

AbstractSelenomethionine (SeMet) readily replaces methionine (Met) residues in proteins during translation. Long‐term dietary SeMet intake results in the accumulation of the amino acid in tissue proteins. Despite the high rates of SeMet incorporation in proteins and its stronger susceptibility to oxidation compared to Met, little is known about the effect of SeMet mis‐incorporation on electrical excitability and ion channels. Fast inactivation of voltage‐gated sodium (NaV) channels is essential for exact action potential shaping with even minute impairment of inactivation resulting in a plethora of adverse phenotypes. Met oxidation of the NaV channel inactivation motif (Ile‐Phe‐Met) and further Met residues causes a marked loss of inactivation. Here, we examined the impact of SeMet mis‐incorporation on the function of NaV channels. While extensive SeMet incorporation into recombinant rat NaV1.4 channels preserved their normal function, it greatly sensitized the channels to mild oxidative stress, resulting in loss of inactivation and diminished maximal current, both reversible by dithiothreitol‐induced reduction. SeMet incorporation similarly affected human NaV1.4, NaV1.2, NaV1.5, and NaV1.7. In mouse dorsal root ganglia (DRG) neurons, 1 day of SeMet exposure exacerbated the oxidation‐mediated broadening of action potentials. SeMet‐treated DRGs also exhibited a stronger increase in the persistent NaV current in response to oxidation. SeMet incorporation in NaV proteins coinciding with oxidative insults may therefore result in hyperexcitability pathologies, such as cardiac arrhythmias and neuropathies, like congenital NaV channel gain‐of‐function mutations.image