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J Biol Chem
2021 Dec 01;2976:101355. doi: 10.1016/j.jbc.2021.101355.
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A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy.
Ygberg S
,
Akkuratov EE
,
Howard RJ
,
Taylan F
,
Jans DC
,
Mahato DR
,
Katz A
,
Kinoshita PF
,
Portal B
,
Nennesmo I
,
Lindskog M
,
Karlish SJD
,
Andersson M
,
Lindstrand A
,
Brismar H
,
Aperia A
.
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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 Mg2+. 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.
Figure 4. Electrophysiology in W931R α1-expressing cells. A, representative traces from two-electrode voltage-clamp electrophysiology recordings at −70 mV in Xenopus oocytes overexpressing human Na,K-ATPase, showing concentration-dependent activation of outward currents upon exposure to external K+ with minimal baseline drift over 15 min in oocytes injected with WT α1 mRNA. By contrast, oocytes injected with W931R α1 mRNA exhibit an escalating inward current. B, mean baseline displacement after clamping for 15 min at −70 mV, following the protocol in (A). Columns represent absolute currents (μA), n = 5; significance relative to WT α1, two-tailed unpaired t test, ∗p < 0.01. C, current–voltage relationships under resting conditions (100 mM Na+, 0 mM K+) for noninjected control oocytes (black) and W931R α1-injected oocytes (red), n ≥ 3. Treatment with 10 μM ouabain is represented by a lighter shade of black and red for noninjected and W931R α1-injected oocytes, respectively.
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