The Influence of Na(+), K(+)-ATPase on Glutamate Signaling in Neurodegenerative Diseases and Senescence.

Paula F Kinoshita,Jacqueline A Leite,Andrea R Vasconcelos,Ana Maria M Orellana,Luis E M Quintas,Elisa M Kawamoto,Cristoforo Scavone

doi:10.3389/fphys.2016.00195

Paula F Kinoshita, Jacqueline A Leite + Show 5 more

Open Access

https://doi.org/10.3389/fphys.2016.00195

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Abstract

Decreased Na+, K+-ATPase (NKA) activity causes energy deficiency, which is commonly observed in neurodegenerative diseases. The NKA is constituted of three subunits: α, β, and γ, with four distinct isoforms of the catalytic α subunit (α1−4). Genetic mutations in the ATP1A2 gene and ATP1A3 gene, encoding the α2 and α3 subunit isoforms, respectively can cause distinct neurological disorders, concurrent to impaired NKA activity. Within the central nervous system (CNS), the α2 isoform is expressed mostly in glial cells and the α3 isoform is neuron-specific. Mutations in ATP1A2 gene can result in familial hemiplegic migraine (FHM2), while mutations in the ATP1A3 gene can cause Rapid-onset dystonia-Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC), as well as the cerebellar ataxia, areflexia, pescavus, optic atrophy and sensorineural hearing loss (CAPOS) syndrome. Data indicates that the central glutamatergic system is affected by mutations in the α2 isoform, however further investigations are required to establish a connection to mutations in the α3 isoform, especially given the diagnostic confusion and overlap with glutamate transporter disease. The age-related decline in brain α2∕3 activity may arise from changes in the cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG) pathway. Glutamate, through nitric oxide synthase (NOS), cGMP and PKG, stimulates brain α2∕3 activity, with the glutamatergic N-methyl-D-aspartate (NMDA) receptor cascade able to drive an adaptive, neuroprotective response to inflammatory and challenging stimuli, including amyloid-β. Here we review the NKA, both as an ion pump as well as a receptor that interacts with NMDA, including the role of NKA subunits mutations. Failure of the NKA-associated adaptive response mechanisms may render neurons more susceptible to degeneration over the course of aging.

Highlights

INTRODUCTIONIn 1957, the Danish physician Jens C
Na+, K+-ATPaseIn 1957, the Danish physician Jens C
All isoforms are encoded by different genes, have a high degree of sequence homology and are expressed in a cell/tissue-specific manner (Broude et al, 1989; Mobasheri et al, 2000; Blanco, 2005): α1 is expressed in all mammalian tissue, being virtually the only α isoform expressed in the kidney across species; α2 is found in striated and smooth muscles, adipose tissue, nervous tissue and some other tissues; α3 and α4 have a more restricted distribution, with the former being primarily found in nervous tissue, in neurons, where it may be considered a brain neuronal marker (Dobretsov and Stimers, 2005), and the latter is only expressed in the midpiece of the sperm, where it is important for sperm motility (Sanchez et al, 2006)

Summary

INTRODUCTION

In 1957, the Danish physician Jens C. Subsequent work indicated a feed-forward reaction, whereby as Na+ binds to the enzyme, it stimulates a Mg2+dependent phosphorylation via ATP, while K+ binding facilitates dephosphorylation, giving a transition of two conformations named E1 and E2, respectively (Post et al, 1972) Later work made it clear that activity of this molecular motor is vital for cell integrity, given its maintenance of the osmotic balance and its powerful role in cell homeostasis, including preserving and contributing to the resting membrane potential, electrolyte constitution of the cerebrospinal fluid (CSF) and influencing the cellular and/or transcellular transport of other ions, energy substrates and neurotransmitters (Blanco and Mercer, 1998; Skou, 1998; Blanco, 2005). All isoforms are encoded by different genes, have a high degree of sequence homology and are expressed in a cell/tissue-specific manner (Broude et al, 1989; Mobasheri et al, 2000; Blanco, 2005): α1 is expressed in all mammalian tissue, being virtually the only α isoform expressed in the kidney across species; α2 is found in striated and smooth muscles, adipose tissue, nervous tissue and some other tissues; α3 and α4 have a more restricted distribution, with the former being primarily found in nervous tissue, in neurons, where it may be considered a brain neuronal marker (Dobretsov and Stimers, 2005), and the latter is only expressed in the midpiece of the sperm, where it is important for sperm motility (Sanchez et al, 2006)

A Pump or a Receptor

Introduction

Findings

CONCLUSIONS AND FUTURE