Brain sodium MRI in human epilepsy: Disturbances of ionic homeostasis reflect the organization of pathological regions

Subcellular compartments commonly identified and analyzed by high resolution electron probe x-ray microanalysis (EPXMA) include mitochondria, cytoplasm and endoplasmic or sarcoplasmic reticulum. These organelles and cell regions are of primary importance in regulation of cell ionic homeostasis. Correlative structural-functional studies, based on the static probe method of EPXMA combined with biochemical and electrophysiological techniques, have focused on the role of these organelles, for example, in maintaining cell calcium homeostasis or in control of excitation-contraction coupling. New methods of real time quantitative x-ray imaging permit simultaneous examination of multiple cell compartments, especially those areas for which both membrane transport properties and element content are less well defined, e.g. nuclei including euchromatin and heterochromatin, lysosomes, mucous granules, storage vacuoles, microvilli. Investigations currently in progress have examined the role of Zn-containing polyphosphate vacuoles in the metabolism of Leishmania major, the distribution of Na, K, S and other elements during anoxia in kidney cell nuclel and lysosomes; the content and distribution of S and Ca in mucous granules of cystic fibrosis (CF) nasal epithelia; the uptake of cationic probes by mltochondria in cultured heart ceils; and the junctional sarcoplasmic retlculum (JSR) in frog skeletal muscle.

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Sodium MRI with 3D-cones as a measure of tumour cellularity in high grade serous ovarian cancer

European Journal of Radiology Open ◽

10.1016/j.ejro.2019.04.001 ◽

2019 ◽

Vol 6 ◽

pp. 156-162 ◽

Cited By ~ 1

Author(s):

Surrin S. Deen ◽

Frank Riemer ◽

Mary A. McLean ◽

Andrew B. Gill ◽

Joshua D. Kaggie ◽

...

Keyword(s):

Ovarian Cancer ◽

High Grade ◽

Serous Ovarian Cancer ◽

Sodium Mri ◽

Tumour Cellularity

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An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel

BMC Biology ◽

10.1186/s12915-021-01040-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Janire Urrutia ◽

Alejandra Aguado ◽

Carolina Gomis-Perez ◽

Arantza Muguruza-Montero ◽

Oscar R. Ballesteros ◽

...

Keyword(s):

Structural Instability ◽

Binding Assays ◽

Iq Motif ◽

Channel Function ◽

Human Epilepsy ◽

Pathogenic Variants ◽

In Silico Studies ◽

Nascent Chain

Abstract Background The amino acid sequence of proteins generally carries all the necessary information for acquisition of native conformations, but the vectorial nature of translation can additionally determine the folding outcome. Such consideration is particularly relevant in human diseases associated to inherited mutations leading to structural instability, aggregation, and degradation. Mutations in the KCNQ2 gene associated with human epilepsy have been suggested to cause misfolding of the encoded Kv7.2 channel. Although the effect on folding of mutations in some domains has been studied, little is known of the way pathogenic variants located in the calcium responsive domain (CRD) affect folding. Here, we explore how a Kv7.2 mutation (W344R) located in helix A of the CRD and associated with hereditary epilepsy interferes with channel function. Results We report that the epilepsy W344R mutation within the IQ motif of CRD decreases channel function, but contrary to other mutations at this site, it does not impair the interaction with Calmodulin (CaM) in vitro, as monitored by multiple in vitro binding assays. We find negligible impact of the mutation on the structure of the complex by molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments. Conclusions Our data suggest that the key pathogenic mechanism of Kv7.2 W344R mutation involves the failure to adopt a configuration that can be recognized by CaM in vivo but not in vitro.

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Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22157887 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7887

Author(s):

Carmen Nanclares ◽

Andres Mateo Baraibar ◽

Alfonso Araque ◽

Paulo Kofuji

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Synaptic Plasticity ◽

Neuronal Excitability ◽

Active Role ◽

Ionic Homeostasis ◽

Neuronal Communication ◽

Structural Support

Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

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Dissecting the Molecular Determinants of GABAA Receptors Current Rundown, a Hallmark of Refractory Human Epilepsy

Brain Sciences ◽

10.3390/brainsci11040441 ◽

2021 ◽

Vol 11 (4) ◽

pp. 441

Author(s):

Pierangelo Cifelli ◽

Silvia Di Angelantonio ◽

Veronica Alfano ◽

Alessandra Morano ◽

Eleonora De Felice ◽

...

Keyword(s):

Gabaa Receptors ◽

Drug Resistant ◽

Human Embryonic Kidney Cells ◽

Inhibitory Function ◽

Human Epilepsy ◽

Wide Range ◽

Molecular Determinants ◽

The Central Nervous System ◽

Heterologous Expression Systems ◽

Important Therapeutic Target

GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits reaching the maximum current decrease when functional α1β2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in α1β2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment.

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Fullerenol regulates oxidative stress and tissue ionic homeostasis in spring wheat to improve net-primary productivity under salt-stress

Ecotoxicology and Environmental Safety ◽

10.1016/j.ecoenv.2021.111901 ◽

2021 ◽

Vol 211 ◽

pp. 111901

Author(s):

Fahad Shafiq ◽

Muhammad Iqbal ◽

Muhammad Ali ◽

Muhammad Arslan Ashraf

Keyword(s):

Oxidative Stress ◽

Salt Stress ◽

Spring Wheat ◽

Primary Productivity ◽

Net Primary Productivity ◽

Ionic Homeostasis

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The murburn precepts for cellular ionic homeostasis and electrophysiology

Journal of Cellular Physiology ◽

10.1002/jcp.30547 ◽

2021 ◽

Author(s):

Kelath Murali Manoj ◽

Nikolai Bazhin ◽

Hirohisa Tamagawa

Keyword(s):

Ionic Homeostasis

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Sodium Radiofrequency Coils for Magnetic Resonance: From Design to Applications

Electronics ◽

10.3390/electronics10151788 ◽

2021 ◽

Vol 10 (15) ◽

pp. 1788

Author(s):

Giulio Giovannetti ◽

Alessandra Flori ◽

Nicola Martini ◽

Roberto Francischello ◽

Giovanni Donato Aquaro ◽

...

Keyword(s):

Magnetic Resonance ◽

Sodium Concentration ◽

Resonance Spectroscopy ◽

Sodium Mri ◽

Human Organs ◽

Low Sodium ◽

Radiofrequency Coils ◽

Anatomical Imaging ◽

Strong Gradient

Sodium (23Na) is the most abundant cation present in the human body and is involved in a large number of vital body functions. In the last few years, the interest in Sodium Magnetic Resonance Imaging (23Na MRI) has considerably increased for its relevance in physiological and physiopathological aspects. Indeed, sodium MRI offers the possibility to extend the anatomical imaging information by providing additional and complementary information on physiology and cellular metabolism with the heteronuclear Magnetic Resonance Spectroscopy (MRS). Constraints are the rapidly decaying of sodium signal, the sensitivity lack due to the low sodium concentration versus 1H-MRI induce scan times not clinically acceptable and it also constitutes a challenge for sodium MRI. With the available magnetic fields for clinical MRI scanners (1.5 T, 3 T, 7 T), and the hardware capabilities such as strong gradient strengths with high slew rates and new dedicated radiofrequency (RF) sodium coils, it is possible to reach reasonable measurement times (~10–15 min) with a resolution of a few millimeters, where it has already been applied in vivo in many human organs such as the brain, cartilage, kidneys, heart, as well as in muscle and the breast. In this work, we review the different geometries and setup of sodium coils described in the available literature for different in vivo applications in human organs with clinical MR scanners, by providing details of the design, modeling and construction of the coils.

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