Rapid decrease of high affinity ouabain binding sites in hippocampal CA1 region following short-term global cerebral ischemia in rat

Pylova, S. I.; Majkowska, Joanna; Hilgier, Wojciech; Kapuściński, A; Albrecht, Jan

doi:10.1016/0006-8993(89)90446-0

Cited by 25 publications

(4 citation statements)

References 15 publications

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“…This concentration was 40% of the concentration of NAKα3 (35.2 ± 10 pmol/mg membrane protein; n = 4) that we measured (as shown in Fig. 3G using prequantified, cell-free synthesized NAKα3 as the quantification standard; for details see SI Materials and Methods) and it was ∼37-88% of the concentrations found in the literature (16-38 pmol/mg membrane protein) (33,34). Simple arithmetic calculations thus give an ASPD:NAKα3 ratio ranging from 1:1-1:3.…”

Section: Aspd Bind To Nakα3supporting

confidence: 62%

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

155

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Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10-to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuronspecific Na + /K + -ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn 879 and Trp 880 is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.NMR | computational modeling | abnormal protein-protein interaction in synapse | hyperexcitotoxicity | protein-protein interaction inhibitors

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Section: Aspd Bind To Nakα3supporting

confidence: 62%

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

155

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“…Thus the down-regulation of KCC2 could usefully decrease energy expenditure in pathological states associated with an energy deficit 25 . In a similar way, the Na-K ATPase is down-regulated by neuronal damage 66,67 . Alternatively, changes in Cl-homeostasis could contribute to more general processes of neuronal de-differentiation induced by trauma.…”

Section: Changes In CL − Regulating Systems In Pathological Statesmentioning

confidence: 84%

Chloride Homeostasis and GABA Signaling in Temporal Lobe Epilepsy

Miles¹,

Blaesse²,

Huberfeld³

et al. 2012

Jasper's Basic Mechanisms of the Epilepsies

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Changes in neuronal chloride homeostasis affect GABA A receptor-mediated transmission and may contribute to epileptic activities. Work on human epileptic tissue suggests that Cl − homeostasis is impaired in some temporal lobe pyramidal cells. GABAergic depolarization of these neurons contributes to rhythmic, interictal events. Intra-neuronal Cl − is controlled in part by two electroneutral cation-chloride cotransporters. NKCC1 mediates Cl − influx, while KCC2 extrudes Cl − thus assuring that GABAergic signals hyperpolarize neurons. After stress, such as trauma or denervation, the expression and/or function of the cotransporters are altered. KCC2 is down-regulated in some pyramidal cells from both patients with temporal lobe epilepsy and animals with acquired focal epilepsies. The resulting depolarising GABAergic signals contribute to the generation of interictallike activity. Is a defective Cl − homeostasis also crucial for the genesis of ictal events? Ictal discharges are associated with intense interneuron firing and activation of GABA receptors. Depolarizing responses to GABA are evident during ictal events generated by convulsants in both animal epilepsy models and human tissue. K-Cl cotransport by KCC2 is increased by the Cl − load in neurons. Paradoxically, the resulting increase in extracellular K + generates a prolonged depolarization that may sustain seizure discharges.

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“…It has been proposed that the posttraumatic downregulation of neuronal Clextrusion and the consequent depolarizing shift in E GABA-A are aspects of dedifferentiation of neurons and neuronal networks that are permissive for the ''recapitulation'' of developmental programs for the rewiring of surviving neurons (Payne et al, 2003;Pieraut et al, 2007;Shulga et al, 2008). Furthermore, in view of the tight link between the Na-K ATPase and CCC functions, it is interesting that seizure activity and neuronal damage have been shown to lead to a downregulation of the sodium pump (e.g., Pylova et al, 1989;Ross and Soltesz, 2000), which may well be a neuroprotective response to minimize local oxygen and glucose demand during traumarelated hyperexcitability and plasticity.…”

Section: Pathogenic Versus Protective Mechanismsmentioning

confidence: 99%

Cation-Chloride Cotransporters and Neuronal Function

Blaesse

Airaksinen

Rivera

et al. 2009

Neuron

726

782

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Recent years have witnessed a steep increase in studies on the diverse roles of neuronal cation-chloride cotransporters (CCCs). The versatility of CCC gene transcription, posttranslational modification, and trafficking are on par with what is known about ion channels. The cell-specific and subcellular expression patterns of different CCC isoforms have a key role in modifying a neuron's electrophysiological phenotype during development, synaptic plasticity, and disease. While having a major role in controlling responses mediated by GABA(A) and glycine receptors, CCCs also show close interactions with glutamatergic signaling. A cross-talk among CCCs and trophic factors is important in short-term and long-term modification of neuronal properties. CCCs appear to be multifunctional proteins that are also involved in shaping neuronal structure at various stages of development, from stem cells to synaptogenesis. The rapidly expanding work on CCCs promotes our understanding of fundamental mechanisms that control brain development and functions under normal and pathophysiological conditions.

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Rapid decrease of high affinity ouabain binding sites in hippocampal CA1 region following short-term global cerebral ischemia in rat

Cited by 25 publications

References 15 publications

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Chloride Homeostasis and GABA Signaling in Temporal Lobe Epilepsy

Cation-Chloride Cotransporters and Neuronal Function

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