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

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.

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

“…FXYD2 and ATP4A ) in the prioritized gene list also warrants further investigation, but both have been implicated in processes important for HD pathogenesis, namely glutamate- and Wnt-signaling respectively. 31, 43, 44 Like GPR161, ATP4A has also been shown to have important functions in the cilia, 44 which may be relevant for HD since HTT is required for ciliogenesis. 19 Finally, since sonic hedgehog signaling was implicated through both the top TWAS genes and module based analyses, further research is required in this area.…”

Neuroinflammation and Neurotransmission Mechanisms Involved in Neuropsychiatric Disorders

“…These cells have receptors for serotonin, norepinephrine, GABA, acetylcholine, AMPA, and NMDA glutamate receptor, as well for group I, II, and III metabotropic glutamate receptors, variations in the concentrations of these mediators could interfere with microglial function and morphology, as well as in the recognition of neuronal activity by the microglia [21,22]. Glutamate, an important excitatory neurotransmitter of the CNS, acts mostly in the hippocampus, cortex, and caudate nucleus through its metabotropic and ionotropic receptors, NMDA, AMPA, and Kainate and plays an important role in the processes of learning and memory formation, as well as in motor behavior and brain development [23]. The hyperglutamatergic hypothesis of autism is based on studies that showed high levels of glutamate in the serum, lower levels of the enzymes glutamate acid decarboxylase 65 and 67 (GAD65 and GAD67) [24,25], and the presence of increased gliosis in these patients [11].…”

The relevance of α-KLOTHO to the central nervous system: Some key questions

“…Through interactions with Src tyrosine kinases and IP3-receptors, Na,K-ATPases mediate the activation of Src tyrosine kinase-and intracellular Ca +2 -dependent signaling cascades, respectively (Aperia et al, 2016;Madan et al, 2016). Although classically described as a compound that affects the heart, ouabain is emerging as a potent neuroprotective agent (Kinoshita et al, 2016), and the Na + /K + -ATPase α 3 isoform plays an important role in the control of spatial learning and memory (Holm et al, 2016). Taken together, these observations make a role for brain α-Klotho as a regulator of Na,K-ATPasedependent cell signaling an exciting suggestion.…”