A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy

Abstract

The ion pump Na + ,K + -ATPase is a critical determinant of neuronal excitability; however, its role in the etiology of diseases of the central nervous system (CNS) is largely unknown. We describe here the molecular phenotype of a Trp931Arg mutation of the Na + ,K + -ATPase catalytic α1 subunit in an infant diagnosed with therapy-resistant lethal epilepsy. In addition to the pathological CNS phenotype, we also detected renal wasting of Mg 2+ . We found that membrane expression of the mutant α1 protein was low, and ion pumping activity was lost. Arginine insertion into membrane proteins can generate water-filled pores in the plasma membrane, and our molecular dynamic (MD) simulations of the principle states of Na + ,K + -ATPase transport demonstrated massive water inflow into mutant α1 and destabilization of the ion-binding sites. MD simulations also indicated that a water pathway was created between the mutant arginine residue and the cytoplasm, and analysis of oocytes expressing mutant α1 detected a nonspecific cation current. Finally, neurons expressing mutant α1 were observed to be depolarized compared with neurons expressing wild-type protein, compatible with a lowered threshold for epileptic seizures. The results imply that Na + ,K + -ATPase should be considered a neuronal locus minoris resistentia in diseases associated with epilepsy and with loss of plasma membrane integrity.

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…One such example is the sodium-potassium pump (Na + /K + ATPase), which is a plasma membrane ion pump that transports 3 Na + ions out of the cell and 2 K + ions into the cell at the expense of energy derived from ATP hydrolysis. 131,135 Na + /K + -ATPases also play an important role in the regulation of intracellular calcium homeostasis through indirect interactions with Na + -Ca 2+ exchangers or inositol 1,4,5-triphosphate receptor-mediated intracellular calcium stores. 136 In mouse SCN, Na + /K + ATPase is more active in the rest period (ZT6-10) than the active period (ZT 12-17).…”

Structure and function of H+/K+ pump mutants reveal Na+/K+ pump mechanisms

“…Between these two residues, facing the other side of the TM8 helix, NKA has tryptophan (Trp924) while both HKAs have an isoleucine (Ile943 in ngHKA). Mutation to arginine of the equivalent Trp931 in human NKA α1 was found in a patient with a lethal form of hypomagnesemia with seizures 28 . Compared to isoleucine, the sterically larger and hydrogen-bond-capable tryptophan side chain may help stabilize the site-III-coordinating residues in TM8.…”

The role of ATP1A3 gene in epilepsy: We need to know more

“…Currently, increasing numbers of laboratory studies have unveiled the critical roles of Na + -K + -ATPase in epilepsy (Ygberg et al, 2021 ). In rodent models of epilepsy, the activity of Na + -K + -ATPase has been reported to be altered, and pharmacological inhibition of Na + -K + -ATPase would cause epileptic seizures in rodents (Holm and Lykke-Hartmann, 2016 ).…”