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17 results on '"Jung, Gangsoo"'

10. Amphetamine Action at the Cocaine- and Antidepressant-Sensitive Serotonin Transporter Is Modulated by αCaMKII

Author

Steinkellner, Thomas, Montgomery, Therese R., Hofmaier, Tina, Kudlacek, Oliver, Yang, Jae-Won, Rickhag, Mattias, Jung, Gangsoo, Lubec, Gert, Gether, Ulrik, Freissmuth, Michael, and Sitte, Harald H.

Subjects
Male, Mice, Knockout, Serotonin Plasma Membrane Transport Proteins, Articles, Motor Activity, Antidepressive Agents, Mice, Inbred C57BL, Rats, Sprague-Dawley, Amphetamine, Mice, HEK293 Cells, Cocaine, Animals, Humans, Female, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cells, Cultured
Abstract

Serotonergic neurotransmission is terminated by reuptake of extracellular serotonin (5-HT) by the high-affinity serotonin transporter (SERT). Selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine or escitalopram inhibit SERT and are currently the principal treatment for depression and anxiety disorders. In addition, SERT is a major molecular target for psychostimulants such as cocaine and amphetamines. Amphetamine-induced transport reversal at the closely related dopamine transporter (DAT) has been shown previously to be contingent upon modulation by calmodulin kinase IIα (αCaMKII). Here, we show that not only DAT, but also SERT, is regulated by αCaMKII. Inhibition of αCaMKII activity markedly decreased amphetamine-triggered SERT-mediated substrate efflux in both cells coexpressing SERT and αCaMKII and brain tissue preparations. The interaction between SERT and αCaMKII was verified using biochemical assays and FRET analysis and colocalization of the two molecules was confirmed in primary serotonergic neurons in culture. Moreover, we found that genetic deletion of αCaMKII impaired the locomotor response of mice to 3,4-methylenedioxymethamphetamine (also known as "ecstasy") and blunted d-fenfluramine-induced prolactin release, substantiating the importance of αCaMKII modulation for amphetamine action at SERT in vivo as well. SERT-mediated substrate uptake was neither affected by inhibition of nor genetic deficiency in αCaMKII. This finding supports the concept that uptake and efflux at monoamine transporters are asymmetric processes that can be targeted separately. Ultimately, this may provide a molecular mechanism for putative drug developments to treat amphetamine addiction.

Published
2015

14. Functional regulation of amphetamine-induced efflux by CaMKII

Author

Sitte, Harald H., Steinkellner, Thomas, Montgomery, Therese R., Hofmaier, Tina, Kudlacek, Oliver, Yang, Jae-Won, Jung, Gangsoo, Lubec, Gert, Gether, Ulrik, Freissmuth, Michael, Pollak, Daniela D., Sitte, Harald H., Steinkellner, Thomas, Montgomery, Therese R., Hofmaier, Tina, Kudlacek, Oliver, Yang, Jae-Won, Jung, Gangsoo, Lubec, Gert, Gether, Ulrik, Freissmuth, Michael, and Pollak, Daniela D.

Published
2015

17. Protein L-isoaspartyl O-methyltransferase inhibits amyloid beta fibrillogenesis in vitro.

Author

Jung G, Ryu J, Heo J, Lee SJ, Cho JY, and Hong S

Subjects
Amyloid beta-Peptides biosynthesis, Amyloid beta-Peptides isolation & purification, Benzothiazoles, Blotting, Western, Circular Dichroism, Escherichia coli chemistry, Fluorescent Dyes, Humans, Microscopy, Electron, Transmission, Molecular Weight, Protein D-Aspartate-L-Isoaspartate Methyltransferase isolation & purification, Protein Structure, Secondary, Thiazoles chemistry, Amyloid beta-Peptides chemistry, Plaque, Amyloid chemistry, Protein D-Aspartate-L-Isoaspartate Methyltransferase pharmacology
Abstract

Fibrillar aggregates of beta-amyloid peptide (Abeta) are major constituents of the senile plaques found in the brains of patients suffering from Alzheimer's disease (AD). Previous studies have shown that spontaneous isomerization or racemization of aspartyl residues in Abeta peptides leads to conformational changes in the secondary structure and increased aggregative ability of the peptides. Protein L-isoaspartyl O-methyltransferase (PIMT, EC 2.1.1.77) is a repairing enzyme converting L-isoaspartyl/D-aspartyl residues in damaged proteins to normal L-aspartyl residues. In this study it was investigated, whether PIMT is able to modulate Abeta fibrillogenesis in vitro by methylation of isoaspartyl residue using purified 5Abeta and PIMT. A Thioflavin-T (Th-T) binding assay conducted after aging Abeta in vitro (37 degrees C, pH 7.4 in PBS) revealed that PIMT inhibited the increase of fluorescence caused by amyloid fibrillogenesis. Western blot analysis revealed that high molecular Abeta aggregates (> 200 kDa) only occurred during Abeta incubation, while they were reduced in response to incubation with PIMT and AdoMet. Additionally, circular dichroism (CD) showed that the beta-sheet structure was increased in Abeta peptides in a time-dependent fashion, while PIMT suppressed the beta-sheet transition after 24 h. Finally, transmission electron microscopy (TEM) revealed that PIMT reduced the size of the Abeta aggregates and induced a different pathway, leading to the formation of amorphous structures. Taken together, these findings indicate that isoaspartyl methylation leads to partial blockade of fibrillogenesis of Abeta by inhibiting the beta transition in the Abeta peptide.

Published
2011

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