Brain Na(+), K(+)-ATPase Activity In Aging and Disease (original) (raw)
Related papers
Regulation of Neuronal Na+/K+-ATPase by Specific Protein Kinases and Protein Phosphatases
The Journal of Neuroscience, 2019
The Na ϩ /K ϩ-ATPase (NKA) is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na ϩ and K ϩ electrochemical gradients across the plasmalemma of living cells. Numerous studies in non-neuronal tissues have shown that this transport mechanism is reversibly regulated by phosphorylation/dephosphorylation of the catalytic ␣ subunit and/or associated proteins. In neurons, Na ϩ /K ϩ transport by NKA is essential for almost all neuronal operations, consuming up to two-thirds of the neuron's energy expenditure. However, little is known about its cellular regulatory mechanisms. Here we have used an electrophysiological approach to monitor NKA transport activity in male rat hippocampal neurons in situ. We report that this activity is regulated by a balance between serine/threonine phosphorylation and dephosphorylation. Phosphorylation by the protein kinases PKG and PKC inhibits NKA activity, whereas dephosphorylation by the protein phosphatases PP-1 and PP-2B (calcineurin) reverses this effect. Given that these kinases and phosphatases serve as downstream effectors in key neuronal signaling pathways, they may mediate the coupling of primary messengers, such as neurotransmitters, hormones, and growth factors, to the NKAs, through which multiple brain functions can be regulated or dysregulated.
Regulation of Neuronal Na+/K+-ATPase by Specific Protein Kinases and Protein Phosphatases
The Journal of Neuroscience, 2019
The Na ϩ /K ϩ-ATPase (NKA) is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na ϩ and K ϩ electrochemical gradients across the plasmalemma of living cells. Numerous studies in non-neuronal tissues have shown that this transport mechanism is reversibly regulated by phosphorylation/dephosphorylation of the catalytic ␣ subunit and/or associated proteins. In neurons, Na ϩ /K ϩ transport by NKA is essential for almost all neuronal operations, consuming up to two-thirds of the neuron's energy expenditure. However, little is known about its cellular regulatory mechanisms. Here we have used an electrophysiological approach to monitor NKA transport activity in male rat hippocampal neurons in situ. We report that this activity is regulated by a balance between serine/threonine phosphorylation and dephosphorylation. Phosphorylation by the protein kinases PKG and PKC inhibits NKA activity, whereas dephosphorylation by the protein phosphatases PP-1 and PP-2B (calcineurin) reverses this effect. Given that these kinases and phosphatases serve as downstream effectors in key neuronal signaling pathways, they may mediate the coupling of primary messengers, such as neurotransmitters, hormones, and growth factors, to the NKAs, through which multiple brain functions can be regulated or dysregulated.
Age-related oxidative inactivation of Na+, K+-ATPase in rat brain crude synaptosomes
Experimental Gerontology, 2003
The study was undertaken to examine the status of Na þ , K þ-ATPase in aged rat brain and to verify if any alteration of this enzyme in aged brain could be related to an oxidative damage. The crude synaptosomes from rat brain were exposed in vitro to an oxidative stress in the form of a combination of Fe 2þ (100 mM) and ascorbate (2 mM) for up to 2 h when increased lipid peroxidation (nearly four-fold), extensive protein carbonyl formation and a marked decrease of Na þ , K þ-ATPase activity (approximately 88%) were observed. All these changes were prevented by the presence of a chain-breaking anti-oxidant, butylated hydroxytoluene (0.2 mM), in the incubation mixture. When the same crude synaptosomal membranes from the young (4-6 months) and aged (18-22 months) rat brains were analysed, a significant reduction of Na þ , K þ-ATPase activity (nearly 48%) along with significantly elevated levels of lipid peroxidation products and protein carbonyls could be detected in the aged animals in comparison to young ones. The latter data in combination with the results of in vitro experiments imply that the age-related decline of rat brain Na þ , K þ-ATPase activity is presumably the consequence of an enhanced oxidative damage in aging brain
Cl−-ATPase and Na+/K+-ATPase activities in Alzheimer's disease brains
Neuroscience Letters, 1998
The enzyme activities and the protein levels of Cl −-ATPase and Na + /K +-ATPase were examined in Alzheimer's disease (AD) brains. Cl −-ATPase and Na + /K +-ATPase activities in AD brains (n = 13) were significantly lower than those in age-matched control brains (n = 12). In contrast, there was no significant difference in anion-insensitive Mg 2 +-ATPase activity between the two groups. Western blot analysis revealed that the protein levels of Cl −-ATPase, Na + /K +-ATPase and neuron specific Na + /K +-ATPase a3 isoform were also significantly reduced in AD brains, while the amount of protein disulfide isomerase, one of the house keeping membrane proteins, was not different between the two groups. The data first demonstrated that Cl −-ATPase and Na + /K +-ATPase are selectively impaired in AD brains, which may reduce the gradients of Na + , K + and Cl − across the cell membranes to cause excitotoxic cellular response and the resulting neuronal death.
Frontiers in physiology, 2016
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 fu...
Brain Research, 1991
We investigated the effects of intracerebroventricular infusion of tetrodotoxin on activity and function of brain Na+,K+-ATPase. Infusion of 1 or 3/~g/h for 2, 4 or 7 days by osmotic minipump reduced the number of Na ÷,K+-ATPase sites as measured by ouabaln binding in cerebral cortex. Tetrodotoxin infusions substantially reduced the functional transport capacity of Na+,K÷-ATPase, measured by the maximal increase in synaptoneurosomai a6Rb+ uptake in the presence of monensin. The effects were maximal at 4 days, with a possible partial recovery of activity at 7 days. Results of ouabain inhibition curves suggested that the effect of tetrodotoxin was not specific for enzyme with high or low affinity for ouabain.
FEBS Letters, 2002
The Na + and K + dependence of the frontocortical Na,K-ATPase in Alzheimer's disease (AD) was compared with that in human control (Co) and rat AD model. In AD, the relationship between the Na/K ratio and the Na,K-ATPase activity showed noticeable left-shift with three-fold increase in the enzyme a⁄nity for Na + (K 0:5 = 10 and 30 mM in AD and Co, respectively). The Na + dependence of the enzyme in AD showed two di¡erent Hill coe⁄cients (n H ), 1.1 and 0.3, whereas the Co value of n H was higher (1.4). The rat AD model generated by ibotenic acid revealed a Na + dependence similar to AD. The K + dependence of the Na,K-ATPase showed no signi¢cant di¡erence in AD and Co. Compared with Co, AD produced a shift in the break of the Na,K-ATPase Arrhenius plot, suggesting remarkable alterations in the enzyme lipid environment. Our ¢ndings support the hypothesis that dysfunction of the Na,K-ATPase in AD is provoked by altered Na + dependence of the enzyme. An impairment of the pump functionality might serve as an early mechanism of AD that should be interrupted by selective pharmacological agents. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
Human Genetics, 2009
Mutations affecting the Na + , K + ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na + , K + ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na + , K + ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na + , K + ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. £ The Author(s) 2009. Correspondence to: Michael J. Palladino. Electronic supplementary material The online version of this article (
General physiology and biophysics, 1997
The activities and basic enzymatic properties of Na,K-ATPase were examined in synaptosomal plasma membranes (SPM) prepared from rat hippocampus and striatum. A kinetic analysis showed profound differences in apparent affinities for ATP (Km) between hippocampal (1.21 mmol/l) and striatal (0.76 mmol/l) enzyme preparations, as well as in the corresponding Vmax values. However, physiological efficiencies were almost the same. The complex pattern of dose-response curves to ouabain indicated the presence of two high-affinity forms of Na,K-ATPase in the striatum ("very high-": Ki = 3.73 x 10(-8) mol/l and "high-": Ki = 4.21 x 10(-5) mol/l), and one high affinity form in the hippocampus (Ki = 6.6 x 10(-7) mol/l). In addition, both SPM preparations contained one low affinity form with similar Ki. The "very high-affinity" form had positive cooperativity for ouabain inhibition of Na,K-ATPase activity, in contrast to "high" and "low-affinity" fo...