DR-region of Na+/K+ ATPase is a target to treat excitotoxicity and stroke

Meimei Shi,Peter T H Wong,Xu Cao,Zhizhong Xie,Mengyuan Zhu,Siping Xiong,Jin-Song Bian,Jingyu Chen,Zhiyuan Wu,Yong Yang,Xingzhou Zhang,Lei Cao

doi:10.1038/s41419-018-1230-5

Abstract

Na+/K+ ATPase (NKA) is important in maintaining cellular functions. We found that loss of NKA activities in NKAα1+/− mice is associated with increased susceptibility to ischemic injuries following transient middle cerebral artery occlusion (tMCAO). This is corroborated by the neuroprotective effects of an antibody raised against an extracellular DR region (897DVEDSYGQQWTYEQR911, sequence number as in rat) of NKAα subunit (DR-Ab) in both preventive and therapeutic settings. DR-Ab protects cortical neurons against glutamate-induced toxicity by stimulating activities of NKA and Na+/Ca2+ exchanger (NCX), which resulted in accelerated Ca2+ extrusion. DR-Ab also enhanced the association between NKA and GluR2 and therefore reduced the internalization of both proteins from membrane induced by glutamate toxicity. The mechanism appears to involve suppression of GluR2 phosphorylation through PKCα/PICK pathway. Our data indicate that DR-region of NKA may be a novel therapeutic target for drug development for the treatment of ischemic stroke.

Highlights

Na+/K+ ATPase (NKA) is responsible for maintaining the electrochemical gradient, and the membrane potential, of the cell
NKA is enriched at synapses where it is associated with α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPARs), which is a driving force for excitation
These data suggest that a reduced expression of NKAα1 protein, which is likely to be translated to a reduction in NKA activities in the brain may lead to increased susceptibility to ischemic injuries

Summary

Introduction

Na+/K+ ATPase (NKA) is responsible for maintaining the electrochemical gradient, and the membrane potential, of the cell. The excitability of the neuronal membrane results directly from the fact that its resting potential is maintained in the range of −60–90 mV. NKA interacts functionally with the plasma membrane Na+/Ca2+ exchanger (NCX) to prevent Ca2+ overload[1] and neuronal apoptosis in excitotoxic stress. Inhibition of NKA may induce excitotoxicity[2]. NKA is enriched at synapses where it is associated with α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPARs), which is a driving force for excitation. NKA dysfunction can induce a rapid reduction in the expression of cell-surface

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Conclusion