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2. Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

de Breuk, Anita, Acar, Ilhan E., Kersten, Eveline, Schijvenaars, Mascha M.V.A.P., Colijn, Johanna M., Haer-Wigman, Lonneke, Bakker, Bjorn, de Jong, Sarah, Meester-Smoor, Magda, Verzijden, Timo, Missotten, Tom O.A.R., Monés, Jordi, Biarnés, Marc, Pauleikhoff, Daniel, Hense, Hans W., Silva, Rufino, Nunes, Sandrina, Melo, Joana B., Fauser, Sascha, Hoyng, Carel B., Ueffing, Marius, Coenen, Marieke J.H., Klaver, Caroline C.W., den Hollander, Anneke I., Ajana, Soufiane, Arango-Gonzalez, Blanca, Badura, Franz, De la Cerda, Berta, Borrell, Anna, Cougnard-Grégoire, Audrey, Dammeier, Sascha, de Jong, Eiko K., Delcourt, Cécile, Diether, Sigrid, Emri, Eszter, Endermann, Tanja, Ferraro, Lucia L., Garcia, Míriam, Heesterbeek, Thomas J., Honisch, Sabina, Ikram, A., Kilger, Ellen, Langen, Hanno, Lengyel, Imre, Luthert, Phil, Merle, Bénédicte M.J., Nogoceke, Everson, Peto, Tunde, Pool, Frances M., Rodríguez, Eduardo, Vingerling, Johannes, and Zumbansen, Markus

Subjects
genetic structures, sense organs, eye diseases
Abstract

PurposeTo develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD.DesignCase-control study.ParticipantsIndividuals (n = 4740) from 5 European cohorts.MethodsWe designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis.Main Outcome MeasuresGenetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations.ResultsWe observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy.ConclusionsThis study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Published
2021

4. Development of a Genotype Assay for Age-Related Macular Degeneration

Author

de Breuk, Anita, primary, Acar, Ilhan E., additional, Kersten, Eveline, additional, Schijvenaars, Mascha M.V.A.P., additional, Colijn, Johanna M., additional, Haer-Wigman, Lonneke, additional, Bakker, Bjorn, additional, de Jong, Sarah, additional, Meester-Smoor, Magda A., additional, Verzijden, Timo, additional, Missotten, Tom O.A.R., additional, Monés, Jordi, additional, Biarnés, Marc, additional, Pauleikhoff, Daniel, additional, Hense, Hans W., additional, Silva, Rufino, additional, Nunes, Sandrina, additional, Melo, Joana B., additional, Fauser, Sascha, additional, Hoyng, Carel B., additional, Ueffing, Marius, additional, Coenen, Marieke J.H., additional, Klaver, Caroline C.W., additional, den Hollander, Anneke I., additional, Ajana, Soufiane, additional, Cougnard-Grégoire, Audrey, additional, Delcourt, Cécile, additional, Merle, Bénédicte M.J., additional, Arango-Gonzalez, Blanca, additional, Dammeier, Sascha, additional, Diether, Sigrid, additional, Honisch, Sabina, additional, Kilger, Ellen, additional, Endermann, Tanja, additional, Zumbansen, Markus, additional, Badura, Franz, additional, De la Cerda, Berta, additional, Borrell, Anna, additional, Ferraro, Lucia L., additional, Garcia, Míriam, additional, Rodríguez, Eduardo, additional, Ikram, A., additional, Meester-Smoor, Magda, additional, Vingerling, Johannes, additional, Heesterbeek, Thomas J., additional, de Jong, Eiko K., additional, Acar, I. Erkin, additional, de Breuk, Anita, additional, Emri, Eszter, additional, Lengyel, Imre, additional, Langen, Hanno, additional, Nogoceke, Everson, additional, Peto, Tunde, additional, Luthert, Phil, additional, and Pool, Frances M., additional

Published
2021
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7. Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning

Author

Ajana, Soufiane, primary, Cougnard-Grégoire, Audrey, additional, Colijn, Johanna M., additional, Merle, Bénédicte M.J., additional, Verzijden, Timo, additional, de Jong, Paulus T.V.M., additional, Hofman, Albert, additional, Vingerling, Johannes R., additional, Hejblum, Boris P., additional, Korobelnik, Jean-François, additional, Meester-Smoor, Magda A., additional, Ueffing, Marius, additional, Jacqmin-Gadda, Hélène, additional, Klaver, Caroline C.W., additional, Delcourt, Cécile, additional, Acar, Erkin I., additional, Arango-Gonzalez, Blanca, additional, Armento, Angela, additional, Badura, Franz, additional, Bhatia, Vaibhav, additional, Bhattacharya, Shomi S., additional, Biarnés, Marc, additional, Borrell, Anna, additional, Calado, Sofia M., additional, Dammeier, Sascha, additional, de Breuk, Anita, additional, De la Cerda, Berta, additional, den Hollander, Anneke I., additional, Diaz-Corrales, Francisco J., additional, Diether, Sigrid, additional, Emri, Eszter, additional, Endermann, Tanja, additional, Ferraro, Lucia L., additional, Garcia, Míriam, additional, Heesterbeek, Thomas J., additional, Honisch, Sabina, additional, Hoyng, Carel B., additional, Kilger, Ellen, additional, Kortvely, Elod, additional, Lastrucci, Claire, additional, Langen, Hanno, additional, Lengyel, Imre, additional, Luthert, Phil, additional, Monés, Jordi, additional, Nogoceke, Everson, additional, Peto, Tunde, additional, Pool, Frances M., additional, Rodriguez-Bocanegra, Eduardo, additional, Serrano, Luis, additional, Sousa, Jose, additional, Thee, Eric, additional, Ulrich Bartz-Schmidt, Karl U., additional, and Zumbansen, Markus, additional

Published
2021
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8. Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration

Author

Acar, İlhan E., primary, Lores-Motta, Laura, additional, Colijn, Johanna M., additional, Meester-Smoor, Magda A., additional, Verzijden, Timo, additional, Cougnard-Gregoire, Audrey, additional, Ajana, Soufiane, additional, Merle, Benedicte M.J., additional, de Breuk, Anita, additional, Heesterbeek, Thomas J., additional, van den Akker, Erik, additional, Daha, Mohamed R., additional, Claes, Birte, additional, Pauleikhoff, Daniel, additional, Hense, Hans-Werner, additional, van Duijn, Cornelia M., additional, Fauser, Sascha, additional, Hoyng, Carel B., additional, Delcourt, Cécile, additional, Klaver, Caroline C.W., additional, Galesloot, Tessel E., additional, den Hollander, Anneke I., additional, Arango-Gonzalez, Blanca, additional, Armento, Angela, additional, Badura, Franz, additional, Bhatia, Vaibhav, additional, Bhattacharya, Shomi S., additional, Biarnés, Marc, additional, Borrell, Anna, additional, Calado, Sofia M., additional, Dammeier, Sascha, additional, Cerda, Berta De la, additional, Diaz-Corrales, Francisco J., additional, Diether, Sigrid, additional, Emri, Eszter, additional, Endermann, Tanja, additional, Ferraro, Lucia L., additional, Garcia, Míriam, additional, Honisch, Sabina, additional, Kilger, Ellen, additional, Kortvely, Elod, additional, Lastrucci, Claire, additional, Langen, Hanno, additional, Lengyel, Imre, additional, Luthert, Phil, additional, Monés, Jordi, additional, Nogoceke, Everson, additional, Peto, Tunde, additional, Pool, Frances M., additional, Rodriguez-Bocanegra, Eduardo, additional, Serrano, Luis, additional, Sousa, Jose, additional, Thee, Eric, additional, Ueffing, Marius, additional, Ulrich Bartz-Schmidt, Karl U., additional, and Zumbansen, Markus, additional

Published
2020
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10. Mediterranean Diet and Incidence of Advanced Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

Merle, B. nédicte M. J., Colijn, Johanna M., Cougnard-Grégoire, Audrey, de Koning-Backus, Alexandra P. M., Delyfer, Marie-Noëlle, Kiefte-de Jong, Jessica C., Meester-Smoor, Magda, Féart, Catherine, Verzijden, Timo, Samieri, C. cilia, Franco, Oscar H., Korobelnik, Jean-François, Klaver, Caroline C. W., Delcourt, C. cile, Ajana, Soufiane, Arango-Gonzalez, Blanca, Armento, Angela, Arndt, Verena, Bhatia, Vaibhav, Bhattacharya, Shomi S., Biarnés, Marc, Borrell, Anna, Bühren, Sebastian, Calado, Sofia M., Dammeier, Sascha, de Jong, Eiko K., de la Cerda, Berta, den Hollander, Anneke I., Diaz-Corrales, Francisco J., Diether, Sigrid, Emri, Eszter, Endermann, Tanja, Ferraro, Lucia L., Garcia, M. riam, Heesterbeek, Thomas J., Honisch, Sabina, Hoyng, Carel B., Kersten, Eveline, Kilger, Ellen, Langen, Hanno, Lengyel, Imre, Luthert, Phil, Maugeais, Cyrille, van Leeuwen, Elisabeth M., Zumbansen, Markus, Vasiliev, Vassil, Experimental Immunology, and AII - Inflammatory diseases

Abstract

Purpose: To investigate associations of adherence to the Mediterranean diet (MeDi) with incidence of advanced age-related macular degeneration (AMD; the symptomatic form of AMD) in 2 European population-based prospective cohorts. Design: Prospective cohort study of the Rotterdam Study I (RS-I) and the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (Alienor) Study populations. Participants: Four thousand four hundred forty-six participants 55 years of age or older from the RS-I (The Netherlands) and 550 French adults 73 years of age or older from the Alienor Study with complete ophthalmologic and dietary data were included in the present study. Methods: Examinations were performed approximately every 5 years over a 21-year period (1990–2011) in RS-I and every 2 years over a 4-year period (2006–2012) in the Alienor Study. Adherence to the MeDi was evaluated using a 9-component score based on intake of vegetables, fruits, legumes, cereals, fish, meat, dairy products, alcohol, and the monounsaturated-to-saturated fatty acids ratio. Associations of incidence of AMD with MeDi were estimated using multivariate Cox proportional hazard models. Main Outcomes Measures: Incidence of advanced AMD based on retinal fundus photographs. Results: Among the 4996 included participants, 155 demonstrated advanced incident AMD (117 from the RS-I and 38 from the Alienor Study). The mean follow-up time was 9.9 years (range, 0.6–21.7 years) in the RS-I and 4.1 years (range, 2.5–5.0 years) in the Alienor Study. Pooling data for both the RS-I and Alienor Study, participants with a high (range, 6–9) MeDi score showed a significantly reduced risk for incident advanced AMD compared with participants with a low (range, 0–3) MeDi score in the fully adjusted Cox model (hazard ratio, 0.59; 95% confidence interval, 0.37–0.95; P = 0.04 for trend). Conclusions: Pooling data from the RS-I and Alienor Study, higher adherence to the MeDi was associated with a 41% reduced risk of incident advanced AMD. These findings support the role of a diet rich in healthful nutrient-rich foods such as fruits, vegetables, legumes, and fish in the prevention of AMD.

Published
2019

11. Metabolomics in serum of patients with non-advanced age-related macular degeneration reveals aberrations in the glutamine pathway

Author

Kersten, Eveline, Dammeier, Sascha, Ajana, Soufiane, Groenewoud, Joannes M.M., Codrea, Marius, Klose, Franziska, Lechanteur, Yara T., Fauser, Sascha, Ueffing, Marius, Delcourt, Cécile, Hoyng, Carel B., de Jong, Eiko, Den Hollander, Anneke I., Arango-Gonzalez, Blanca, Arndt, Verena, Bhatia, Vaibhav, Bhatta-Charya, Shomi S., Biarnés, Marc, Borrell, Anna, Bühren, Sebastian, Calado, Sofia M., Colijn, Johanna M., Cougnard-Grégoire, Audrey, De la Cerda, Berta, Del-Court, Cécile, Diaz-Corrales, F. J., Diether, Sigrid, Emri, Eszter, Ender-Mann, Tanja, Ferraro, Lucia, Garcia, Míriam, Heesterbeek, Thomas J., Honisch, Sabina, Iacone, Roberto, Kilger, Ellen, Klaver, Caroline C.W., Langen, Hanno, Lengyel, Imre, Luthert, Phil, Maugeais, Cyrille, Meester-Smoor, Magda, Merle, Benedicte, Monés, Jordi, Nogoceke, Everson, Peto, Tunde, Pool, Fran, Rodríguez, Eduardo, Bartz-Schmidt, Karl Ulrich, Verzijden, Timo, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ophthalmology, and Epidemiology

Subjects
0301 basic medicine, genetic structures, Metabolite, Glutamine, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Disease, Bioinformatics, Biochemistry, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], chemistry.chemical_compound, Macular Degeneration, 0302 clinical medicine, Medicine and Health Sciences, Metabolites, Geriatric Ophthalmology, Amino Acids, Multidisciplinary, Agricultural and Biological Sciences(all), Organic Compounds, Retinal Degeneration, Acidic Amino Acids, Discriminant Analysis, Neurochemistry, Neurotransmitters, Middle Aged, 3. Good health, Chemistry, Physical Sciences, Biomarker (medicine), Medicine, Retinal Disorders, Female, Metabolic Pathways, Glutamate, Metabolic Networks and Pathways, Research Article, Science, 03 medical and health sciences, Metabolomics, Age related, medicine, Humans, Least-Squares Analysis, General, Nutrition, Aged, Glutaminolysis, business.industry, Biochemistry, Genetics and Molecular Biology(all), Organic Chemistry, Chemical Compounds, Biology and Life Sciences, Proteins, Macular degeneration, medicine.disease, eye diseases, Diet, Ophthalmology, 030104 developmental biology, Metabolism, chemistry, Geriatrics, Macular Disorders, 030221 ophthalmology & optometry, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, business, Biomarkers, Neuroscience
Abstract

Contains fulltext : 205500.pdf (Publisher’s version ) (Open Access) Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology.

Published
2019

12. Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration

Author

Colijn, Johanna M., primary, den Hollander, Anneke I., additional, Demirkan, Ayse, additional, Cougnard-Grégoire, Audrey, additional, Verzijden, Timo, additional, Kersten, Eveline, additional, Meester-Smoor, Magda A., additional, Merle, Benedicte M.J., additional, Papageorgiou, Grigorios, additional, Ahmad, Shahzad, additional, Mulder, Monique T., additional, Costa, Miguel Angelo, additional, Benlian, Pascale, additional, Bertelsen, Geir, additional, Bron, Alain M., additional, Claes, Birte, additional, Creuzot-Garcher, Catherine, additional, Erke, Maja Gran, additional, Fauser, Sascha, additional, Foster, Paul J., additional, Hammond, Christopher J., additional, Hense, Hans-Werner, additional, Hoyng, Carel B., additional, Khawaja, Anthony P., additional, Korobelnik, Jean-Francois, additional, Piermarocchi, Stefano, additional, Segato, Tatiana, additional, Silva, Rufino, additional, Souied, Eric H., additional, Williams, Katie M., additional, van Duijn, Cornelia M., additional, Delcourt, Cécile, additional, Klaver, Caroline C.W., additional, Acar, Niyazi, additional, Altay, Lebriz, additional, Anastosopoulos, Eleftherios, additional, Azuara-Blanco, Augusto, additional, Berendschot, Tos, additional, Bergen, Arthur, additional, Binquet, Christine, additional, Bird, Alan, additional, Bobak, Martin, additional, Larsen, Morten Bøgelund, additional, Boon, Camiel, additional, Bourne, Rupert, additional, Brétillon, Lionel, additional, Broe, Rebecca, additional, Bron, Alain, additional, Buitendijk, Gabrielle, additional, Cachulo, Maria Luz, additional, Capuano, Vittorio, additional, Carrière, Isabelle, additional, Chakravarthy, Usha, additional, Chan, Michelle, additional, Chang, Petrus, additional, Colijn, Johanna, additional, Cree, Angela, additional, Cumberland, Phillippa, additional, Cunha-Vaz, José, additional, Daien, Vincent, additional, De Jong, Eiko, additional, Deak, Gabor, additional, Delyfer, Marie-Noëlle, additional, Hollander, Anneke den, additional, Dietzel, Martha, additional, Faria, Pedro, additional, Farinha, Claudia, additional, Finger, Robert, additional, Fletcher, Astrid, additional, Foster, Paul, additional, Founti, Panayiota, additional, Gorgels, Theo, additional, Grauslund, Jakob, additional, Grus, Franz, additional, Hammond, Christopher, additional, Heesterbeek, Thomas, additional, Hermann, Manuel, additional, Hoehn, René, additional, Hogg, Ruth, additional, Holz, Frank, additional, Hoyng, Carel, additional, Jansonius, Nomdo, additional, Janssen, Sarah, additional, de Jong, Eiko, additional, Khawaja, Anthony, additional, Klaver, Caroline, additional, Korobelnik, Jean-François, additional, Lamparter, Julia, additional, Le Goff, Mélanie, additional, Lehtimäki, Terho, additional, Leung, Irene, additional, Lotery, Andrew, additional, Mauschitz, Matthias, additional, Meester, Magda, additional, Merle, Bénédicte, additional, Meyer zu Westrup, Verena, additional, Midena, Edoardo, additional, Miotto, Stefania, additional, Mirshahi, Alireza, additional, Mohan-Saïd, Sadek, additional, Mueller, Michael, additional, Muldrew, Alyson, additional, Murta, Joaquim, additional, Nickels, Stefan, additional, Nunes, Sandrina, additional, Owen, Christopher, additional, Peto, Tunde, additional, Pfeiffer, Norbert, additional, Prokofyeva, Elena, additional, Rahi, Jugnoo, additional, Raitakari, Olli, additional, Rauscher, Franziska, additional, Ribeiro, Luisa, additional, Rougier, Marie-Bénédicte, additional, Rudnicka, Alicja, additional, Sahel, José, additional, Salonikiou, Aggeliki, additional, Sanchez, Clarisa, additional, Schick, Tina, additional, Schmitz-Valckenberg, Steffen, additional, Schuster, Alexander, additional, Schweitzer, Cédric, additional, Shehata, Jasmin, additional, Silvestri, Giuliana, additional, Simader, Christian, additional, Souied, Eric, additional, Speckauskas, Martynas, additional, Springelkamp, Henriet, additional, Tapp, Robyn, additional, Topouzis, Fotis, additional, van Leeuwen, Elisa, additional, Verhoeven, Virginie, additional, Vingerling, Hans, additional, Von Hanno, Therese, additional, Williams, Katie, additional, Wolfram, Christian, additional, Yip, Jennifer, additional, Zerbib, Jennyfer, additional, Ajana, Soufiane, additional, Arango-Gonzalez, Blanca, additional, Arndt, Verena, additional, Bhatia, Vaibhav, additional, Bhattacharya, Shomi S., additional, Biarnés, Marc, additional, Borrell, Anna, additional, Bühren, Sebastian, additional, Calado, Sofia M., additional, Colijn, Johanna M., additional, Dammeier, Sascha, additional, de Jong, Eiko K., additional, De la Cerda, Berta, additional, Diaz-Corrales, Francisco J., additional, Diether, Sigrid, additional, Emri, Eszter, additional, Endermann, Tanja, additional, Ferraro, Lucia L., additional, Garcia, Míriam, additional, Heesterbeek, Thomas J., additional, Honisch, Sabina, additional, Kilger, Ellen, additional, Langen, Hanno, additional, Lengyel, Imre, additional, Luthert, Phil, additional, Maugeais, Cyrille, additional, Meester-Smoor, Magda, additional, Merle Inserm, Bénédicte M.J., additional, Monés, Jordi, additional, Nogoceke, Everson, additional, Pool, Frances M., additional, Rodríguez, Eduardo, additional, Ueffing, Marius, additional, Ulrich Bartz-Schmidt, Karl U., additional, van Leeuwen, Elisabeth M., additional, and Zumbansen, Markus, additional

Published
2019
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13. Prevalence of Age-Related Macular Degeneration in Europe

Author

Colijn, Johanna M., primary, Buitendijk, Gabriëlle H.S., additional, Prokofyeva, Elena, additional, Alves, Dalila, additional, Cachulo, Maria L., additional, Khawaja, Anthony P., additional, Cougnard-Gregoire, Audrey, additional, Merle, Bénédicte M.J., additional, Korb, Christina, additional, Erke, Maja G., additional, Bron, Alain, additional, Anastasopoulos, Eleftherios, additional, Meester-Smoor, Magda A., additional, Segato, Tatiana, additional, Piermarocchi, Stefano, additional, de Jong, Paulus T.V.M., additional, Vingerling, Johannes R., additional, Topouzis, Fotis, additional, Creuzot-Garcher, Catherine, additional, Bertelsen, Geir, additional, Pfeiffer, Norbert, additional, Fletcher, Astrid E., additional, Foster, Paul J., additional, Silva, Rufino, additional, Korobelnik, Jean-François, additional, Delcourt, Cécile, additional, Klaver, Caroline C.W., additional, Ajana, Soufiane, additional, Arango-Gonzalez, Blanca, additional, Arndt, Verena, additional, Bhatia, Vaibhav, additional, Bhattacharya, Shomi S., additional, Biarnés, Marc, additional, Borrell, Anna, additional, Bühren, Sebastian, additional, Calado, Sofia M., additional, Colijn, Johanna M., additional, Cougnard-Grégoire, Audrey, additional, Dammeier, Sascha, additional, de Jong, Eiko K., additional, De la Cerda, Berta, additional, den Hollander, Anneke I., additional, Diaz-Corrales, Francisco J., additional, Diether, Sigrid, additional, Emri, Eszter, additional, Endermann, Tanja, additional, Ferraro, Lucia L., additional, Garcia, Míriam, additional, Heesterbeek, Thomas J., additional, Honisch, Sabina, additional, Hoyng, Carel B., additional, Kersten, Eveline, additional, Kilger, Ellen, additional, Langen, Hanno, additional, Lengyel, Imre, additional, Luthert, Phil, additional, Maugeais, Cyrille, additional, Meester-Smoor, Magda, additional, Monés, Jordi, additional, Nogoceke, Everson, additional, Peto, Tunde, additional, Pool, Frances M., additional, Rodríguez, Eduardo, additional, Ueffing, Marius, additional, Ulrich Bartz-Schmidt, Karl U., additional, van Leeuwen, Elisabeth M., additional, Verzijden, Timo, additional, Zumbansen, Markus, additional, Acar, Niyazi, additional, Anastosopoulos, Eleftherios, additional, Azuara-Blanco, Augusto, additional, Bergen, Arthur, additional, Binquet, Christine, additional, Bird, Alan, additional, Brétillon, Lionel, additional, Buitendijk, Gabrielle, additional, Cachulo, Maria Luz, additional, Chakravarthy, Usha, additional, Chan, Michelle, additional, Chang, Petrus, additional, Colijn, Johanna, additional, Cumberland, Philippa, additional, Cunha-Vaz, José, additional, Daien, Vincent, additional, Deak, Gabor, additional, Delyfer, Marie-Noëlle, additional, den Hollander, Anneke, additional, Dietzel, Martha, additional, Erke, Maja Gran, additional, Fauser, Sascha, additional, Finger, Robert, additional, Fletcher, Astrid, additional, Foster, Paul, additional, Founti, Panayiota, additional, Göbel, Arno, additional, Gorgels, Theo, additional, Grauslund, Jakob, additional, Grus, Franz, additional, Hammond, Christopher, additional, Helmer, Catherine, additional, Hense, Hans-Werner, additional, Hermann, Manuel, additional, Hoehn, René, additional, Hogg, Ruth, additional, Holz, Frank, additional, Hoyng, Carel, additional, Jansonius, Nomdo, additional, Janssen, Sarah, additional, Khawaja, Anthony, additional, Klaver, Caroline, additional, Lamparter, Julia, additional, Le Goff, Mélanie, additional, Leal, Sergio, additional, Lechanteur, Yara, additional, Lehtimäki, Terho, additional, Lotery, Andrew, additional, Leung, Irene, additional, Mauschitz, Matthias, additional, Merle, Bénédicte, additional, Meyer zu Westrup, Verena, additional, Midena, Edoardo, additional, Miotto, Stefania, additional, Mirshahi, Alireza, additional, Mohan-Saïd, Sadek, additional, Mueller, Michael, additional, Muldrew, Alyson, additional, Nunes, Sandrina, additional, Oexle, Konrad, additional, Rahi, Jugnoo, additional, Raitakari, Olli, additional, Ribeiro, Luisa, additional, Rougier, Marie-Bénédicte, additional, Sahel, José, additional, Salonikiou, Aggeliki, additional, Sanchez, Clarisa, additional, Schmitz-Valckenberg, Steffen, additional, Schweitzer, Cédric, additional, Shehata, Jasmin, additional, Silvestri, Giuliana, additional, Simader, Christian, additional, Souied, Eric, additional, Springelkamp, Henriet, additional, Tapp, Robyn, additional, Verhoeven, Virginie, additional, Von Hanno, Therese, additional, Vujosevic, Stela, additional, Williams, Katie, additional, Wolfram, Christian, additional, Yip, Jennifer, additional, Zerbib, Jennyfer, additional, and Zwiener, Isabella, additional

Published
2017
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14. Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients

Author

Pelzl, Lisann, primary, Elsir, Bhaeldin, additional, Sahu, Itishri, additional, Bissinger, Rosi, additional, Singh, Yogesh, additional, Sukkar, Basma, additional, Honisch, Sabina, additional, Schoels, Ludger, additional, Jemaà, Mohamed, additional, Lang, Elisabeth, additional, Storch, Alexander, additional, Hermann, Andreas, additional, Stournaras, Christos, additional, and Lang, Florian, additional

Published
2017
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17. Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G-protein subunit Gαi2

Author

Bissinger, Rosi, primary, Lang, Elisabeth, additional, Ghashghaeinia, Mehrdad, additional, Singh, Yogesh, additional, Zelenak, Christine, additional, Fehrenbacher, Birgit, additional, Honisch, Sabina, additional, Chen, Hong, additional, Fakhri, Hajar, additional, Umbach, Anja T., additional, Liu, Guilai, additional, Rexhepaj, Rexhep, additional, Liu, Guoxing, additional, Schaller, Martin, additional, Mack, Andreas F., additional, Lupescu, Adrian, additional, Birnbaumer, Lutz, additional, Lang, Florian, additional, and Qadri, Syed M., additional

Published
2016
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18. Functional characterization and anti-cancer action of the clinical phase II cardiac Na+/K+ ATPase inhibitor istaroxime: in vitro and in vivo properties and cross talk with the membrane androgen receptor

Author

Alevizopoulos, Konstantinos, primary, Dimas, Konstantinos, additional, Papadopoulou, Natalia, additional, Schmidt, Eva-Maria, additional, Tsapara, Anna, additional, Alkahtani, Saad, additional, Honisch, Sabina, additional, Prousis, Kyriakos C., additional, Alarifi, Saud, additional, Calogeropoulou, Theodora, additional, Lang, Florian, additional, and Stournaras, Christos, additional

Published
2016
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23. Stimulated Suicidal Erythrocyte Death in Arteritis

Author

Bissinger, Rosi, primary, Kempe-Teufel, Daniela S., additional, Honisch, Sabina, additional, Qadri, Syed M., additional, Randrianarisoa, Elko, additional, Häring, Hans-Ulrich, additional, Henes, Jörg, additional, and Lang, Florian, additional

Published
2016
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26. Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients.

Author

Pelzl, Lisann, Elsir, Bhaeldin, Sahu, Itishri, Bissinger, Rosi, Singh, Yogesh, Sukkar, Basma, Honisch, Sabina, Schoels, Ludger, Jemaà, Mohamed, Lang, Elisabeth, Storch, Alexander, Hermann, Andreas, Stournaras, Christos, and Lang, Florian

Subjects
LITHIUM, FIBROBLASTS, CALCIUM, NEURODEGENERATION, APOPTOSIS
Abstract

Background: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orail, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE). Increased Orail expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment. Methods: Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca2+ activity ([Ca2+]i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+] following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry. Results: SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 µM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2-APB and virtually lithium insensitive in the presence of 2-APB. Conclusions: In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment. [ABSTRACT FROM AUTHOR]

Published
2017
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27. Chorein addiction in VPS13A overexpressing rhabdomyosarcoma cells

Author

Honisch, Sabina, primary, Yu, Willi, additional, Liu, Guilai, additional, Alesutan, Ioana, additional, Towhid, Syeda T., additional, Tsapara, Anna, additional, Schleicher, Sabine, additional, Handgretinger, Rupert, additional, Stournaras, Christos, additional, and Lang, Florian, additional

Published
2015
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31. Chorein Sensitive Arrangement of Cytoskeletal Architecture

Author

Honisch, Sabina, primary, Gu, Shuchen, additional, vom Hagen, Jennifer Müller, additional, Alkahtani, Saad, additional, Al Kahtane, Abdullah A., additional, Tsapara, Anna, additional, Hermann, Andreas, additional, Storch, Alexander, additional, Schöls, Ludger, additional, Lang, Florian, additional, and Stournaras, Christos, additional

Published
2015
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34. Chorein Sensitive Orai1 Expression and Store Operated Ca2+ Entry in Rhabdomyosarcoma Cells.

Author

Willi Yu, Honisch, Sabina, Schmidt, Sebastian, Jing Yan, Schmid, Evi, Alkahtani, Saad, AlKahtane, Abdullah A., Alarifi, Saud, Stournaras, Christos, and Lang, Florian

Subjects
*PROTEIN expression, *RHABDOMYOSARCOMA, *CANCER cells, *APOPTOSIS, *PHOSPHOINOSITIDES
Abstract

Background: Chorein, a protein encoded by VPS13A (vacuolar protein sorting-associated protein 13A), is defective in chorea acanthocytosis, a rare disease characterized by acanthocytosis of red blood cells and neuronal cell death with progressive hyperkinetic movement disorder, cognitive dysfunction, behavioral abnormalities and chronic hyperkalemia. Chorein is highly expressed in ZF rhabdomyosarcoma cells and counteracts apoptosis of those cells. Chorein is effective in part by interacting with and fostering stimulation of phosphoinositide-3-kinase (PI3K)-p85-subunit. PI3K dependent signaling includes the serum and glucocorticoid inducible kinase SGK1. The kinase activates NFκB with subsequent up-regulation of the Ca2+ channel subunit Orai1, which accomplishes store operated Ca2+ entry (SOCE). Orai1 and SOCE have been shown to confer survival of tumor cells. The present study thus explored whether chorein impacts on Orai1 expression and SOCE. Methods: In rhabdomyosarcoma cells chorein, Orai1, NFκB and SGK1 transcript levels were quantified by RT-PCR, Orai1 protein abundance by Western blotting, FACS analysis and confocal laser microscopy, [Ca2+]i utilizing Fura-2 fluorescence, and SOCE from the increase of [Ca2+]i following store depletion with extracellular Ca2+ removal and inhibition of the sarcoendoplasmatic reticular Ca2+ ATPase with thapsigargin. Results: The mRNA coding for chorein was most abundant in drug resistant, poorly differentiated human ZF rhabdomyosarcoma cells. Chorein silencing significantly decreased Orai1 transcript levels and Orai1 protein expression, as well as SGK1 and NFκB transcript levels. SOCE in ZF rhabdomyosarcoma cells was significantly blunted by chorein silencing, Orai1 inhibitor 2-APB (50 µM), SGK1 inhibitor EMD638683 (50 µM, 10 h) and NFκB inhibitor wogonin (50 µM, 24 h). Conclusion: Chorein is a stimulator of Orai1 expression and thus of store operated Ca2+ entry. The effect may involve SGK1 and NFκB. [ABSTRACT FROM AUTHOR]

Published
2016
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35. A Steroidal Na+/K+ ATPase Inhibitor Triggers Pro-apoptotic Signaling and Induces Apoptosis in Prostate and Lung Tumor Cells

Author

Honisch, Sabina, primary, Alkahtani, Saad, additional, Kounenidakis, Michalis, additional, Liu, Guilai, additional, Alarifi, Saud, additional, Al-Yahya, Hamad, additional, Dimas, Konstantinos, additional, AlKahtane, Abdullah, additional, Prousis, Kyriakos, additional, Al-Dahmash, Bader, additional, Calogeropoulou, Theodora, additional, Alevizopoulos, Konstantinos, additional, Lang, Florian, additional, and Stournaras, Christos, additional

Published
2014
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37. Steroidal Cardiac Na+/K+ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Author

Dimas, Konstantinos, primary, Papadopoulou, Natalia, additional, Baskakis, Constantinos, additional, Prousis, Kyriakos, additional, Tsakos, Michail, additional, Alkahtani, Saad, additional, Honisch, Sabina, additional, Lang, Florian, additional, Calogeropoulou, Theodora, additional, Alevizopoulos, Konstantinos, additional, and Stournaras, Christos, additional

Published
2014
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40. Energy-sensitive regulation of Na+/K+-ATPase by Janus kinase 2

Author

Bhavsar, Shefalee K., primary, Hosseinzadeh, Zohreh, additional, Brenner, Dirk, additional, Honisch, Sabina, additional, Jilani, Kashif, additional, Liu, GuoXing, additional, Szteyn, Kalina, additional, Sopjani, Mentor, additional, Mak, Tak W., additional, Shumilina, Ekaterina, additional, and Lang, Florian, additional

Published
2014
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44. Up-regulation of Orai1 expression and store operated Ca(2+) entry following activation of membrane androgen receptors in MCF-7 breast tumor cells.

Author

Guilai Liu, Honisch, Sabina, Guoxing Liu, Schmidt, Sebastian, Alkahtani, Saad, AlKahtane, Abdullah A., Stournaras, Christos, Lang, Florian, Liu, Guilai, and Liu, Guoxing

Subjects
*GENE expression, *CALCIUM ions, *ANDROGEN receptors, *BREAST cancer, *CANCER cells, *TESTOSTERONE, *CALCIUM metabolism, *PROTEIN metabolism, *CELL receptors, *CYTOPLASM, *BREAST tumors, *CELL lines, *ENZYME inhibitors, *HYDROCARBONS, *POLYMERASE chain reaction, *WESTERN immunoblotting, *PHARMACODYNAMICS, *PHYSIOLOGY, *CELL physiology
Abstract

Background: Membrane androgen receptors (mAR) are functionally expressed in a variety of tumor-cells including the breast tumor-cell line MCF-7. They are specifically activated by testosterone albumin conjugates (TAC). The mAR sensitive signaling includes activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) and reorganization of the actin filament network. Signaling of tumor-cells may further involve up-regulation of pore forming Ca(2+) channel protein Orai1, which accomplishes store operated Ca(2+) entry (SOCE). This study explored the regulation of Orai1 abundance and SOCE by mAR. Methods: Actin filaments were visualized utilizing confocal microscopy, Rac1 activity using GST-GBD assay, Orai1 transcript levels by RT-PCR and total protein abundance by western blotting, Orai1 abundance at the cell surface by confocal microscopy and FACS-analysis, cytosolic Ca(2+) activity ([Ca(2+)]i) utilizing Fura-2-fluorescence, and SOCE from increase of [Ca(2+)]i following readdition of Ca(2+) after store depletion with thapsigargin (1 μM). Results: TAC treatment of MCF-7 cells was followed by Rac1 activation, actin polymerization, transient increase of Orai1transcript levels and protein abundance, and transient increase of SOCE. The transient increase of Orai1 protein abundance was abrogated by Rac1 inhibitor NSC23766 (50 μM) and by prevention of actin reorganization with cytochalasin B (1 μM). Conclusions: mAR sensitive Rac1 activation and actin reorganization contribute to the regulation of Orai1 protein abundance and SOCE. [ABSTRACT FROM AUTHOR]

Published
2015
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45. Impact of Janus Kinase 3 on Cellular Ca2+ Release, Store Operated Ca2+ Entry and Na+/Ca2+ Exchanger Activity in Dendritic Cells.

Author

Yan, Jing, Schmid, Evi, Hosseinzadeh, Zohreh, Honisch, Sabina, Shumilina, Ekaterina, Fuchs, Joerg, and Lang, Florian

Subjects
JANUS kinases, CALCIUM ions, DENDRITIC cells, HEMATOPOIETIC stem cells, CELL proliferation, ANTIGEN presenting cells, T cells, PHYSIOLOGY
Abstract

Background/Aims: Janus kinase 3 (JAK3), a tyrosine kinase mainly expressed in hematopoietic cells, participates in the signaling stimulating cell proliferation. The kinase is expressed in dendritic cells (DCs), antigen presenting cells involved in the initiation and regulation of antigen-specific T-cell responses. Dendritic cell function is regulated by cytosolic Ca2+ activity ([Ca2+]i). Mediators increasing [Ca2+] in DCs include ATP and the chemokine receptor CXCR4 ligand CXCL12. The present study explored, whether JAK3 participates in the regulation of [Ca2+] in DCs. Methods: Fura-2 fluorescence was employed to determine [Ca2+]i, and whole cell patch clamp to decipher electrogenic transport in immature DCs isolated from bone marrow of JAK3-knockout (jak3-/-) or wild-type mice (jak3+/+). Results: Without treatment, [Ca2+] was similar in jak3-/- and jak3+/+ DCs. Addition of ATP (100 |JM) was followed by transient increase of [Ca2+] reflecting Ca2+ release from intracellular stores, an effect significantly less pronounced injak3-/' DCs than injak3+/+ DCs. CXCL12 administration was followed by a sustained increase of [Ca2+] reflecting receptor operated Ca2+ entry, an effect significantly less rapid in jak3-/- DCs than in jak3+/+ DCs. In addition, the Ca2+ release-activated Ca2+ channel (CRAC) current triggered by IP3-induced Ca2+ store depletion and CXCL12 was significantly higher in DCs from jak3+/+ mice than in jak3-/- mice. Inhibition of sarcoendoplasmatic reticulum Ca2+- ATPase (SERCA) by thapsigargin (1 |JM) in the absence of extracellular Ca2+ was followed by a transient increase of [Ca2+] reflecting Ca2+ release from intracellular stores, and subsequent readdition of extracellular Ca2+ in the continued presence of thapsigargin was followed by a sustained increase of [Ca2+] reflecting store operated Ca2+ entry (SOCE). Both, Ca2+ release from intracellular stores and SOCE were again significantly lower in jak3-/- DCs than in jak3+/+ DCs. Pretreatment of jak3+/+ DCs with JAK inhibitor WHI-P154 (22 |JM, 10 minutes or 24 hours) significantly blunted both thapsigargin induced Ca2+ release and subsequent SOCE. Abrupt replacement of Na+ containing (130 mM) and Ca2+ free (0 mM) extracellular bath by Na+ free (0 mM) and Ca2+ containing (2 mM) extracellular bath increased [Ca2+] reflecting Na+/Ca2+ exchanger activity, an effect again significantly less pronounced in jak3-/- DCs than in jak3+/+ DCs. Conclusions: JAK3 deficiency is followed by down-regulation of cytosolic Ca2+ release, receptor and store operated Ca2+ entry and Na+/Ca2+ exchanger activity in DCs. [ABSTRACT FROM AUTHOR]

Published
2015
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46. The Role of Janus Kinase 3 in the Regulation of Na+/K+ ATPase under Energy Depletion.

Author

Hosseinzadeh, Zohreh, Honisch, Sabina, Schmid, Evi, Jilani, Kashif, Szteyn, Kalina, Bhavsar, Shefalee, Singh, Yogesh, Palmada, Monica, Umbach, anja T., Shumilina, Ekaterina, and Lang, Florian

Abstract

Background/Aims: Janus kinase-3 (JAK3) is activated during energy depletion. Energy-consuming pumps include the Na+/K+-ATPase. The present study explored whether JAK3 regulates Na+/K+-ATPase in dendritic cells (DCs). Methods: Ouabain (100 µM)-sensitive (Iouabain) and K+-induced (Ipump) outward currents were determined by utilizing whole cell patch-clamp, Na+/K+-ATPase α1-subunit mRNA levels by RT-PCR, Na+/K+-ATPase protein abundance by flow cytometry or immunofluorescence, and cellular ATP by luciferase-assay in DCs from bone marrow of JAK3-knockout (jak3-/-) or wild-type mice (jak3+/+). Ipump was further determined by voltage clamp in Xenopus oocytes expressing JAK3, active A568VJAK3 or inactive K851AJAK3. Results: Na+/K+-ATPase α1-subunit mRNA and protein levels, as well as Ipump and Iouabain were significantly higher in jak3-/-DCs than in jak3+/+DCs. Energy depletion by 4h pre-treatment with 2,4-dinitro-phenol significantly decreased Ipump in jak3+/+ DCs but not in jak3-/-DCs. Cellular ATP was significantly lower in jak3-/-DCs than in jak3+/+DCs and decreased in both genotypes by 2,4-dinitro-phenol, an effect significantly more pronounced in jak3-/-DCs than in jak3+/+DCs and strongly blunted by ouabain in both jak3+/+ and jak3-/-DCs. Ipump and Iouabain in oocytes were decreased by expression of JAK3 and of A568VJAK3 but not of K851AJAK3. JAK3 inhibitor WHI-P154 (4-[(3'-bromo-4'-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline, 22 μM) enhanced Ipump and Iouabain in JAK3 expressing oocytes. The difference between A568VJAK3 and K851AJAK3 expressing oocytes was virtually abrogated by actinomycin D (50 nM). Conclusions: JAK3 down-regulates Na+/K+-ATPase activity, an effect involving gene expression and profoundly curtailing ATP consumption. [ABSTRACT FROM AUTHOR]

Published
2015
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48. Regulation of the Voltage Gated K Channel Kv1.3 by Recombinant Human Klotho Protein.

Author

almilaji, ahmad, Honisch, Sabina, Liu, Guilai, Elvira, Bernat, ajay, Sumant Singh, Hosseinzadeh, Zohreh, ahmed, Musaab, Munoz, Carlos, Sopjani, Mentor, and Lang, Florian

Subjects
*KIDNEY proteins, *CARRIER proteins, *CELL membranes, *XENOPUS, *COMPLEMENTARY RNA
Abstract

Background/Aims: Klotho, a protein mainly produced in the kidney and released into circulating blood, contributes to the negative regulation of 1,25(OH)2D3 formation and is thus a powerful regulator of mineral metabolism. As β-glucuronidase, alpha Klotho protein further regulates the stability of several carriers and channels in the plasma membrane and thus regulates channel and transporter activity. Accordingly, alpha Klotho protein participates in the regulation of diverse functions seemingly unrelated to mineral metabolism including lymphocyte function. The present study explored the impact of alpha Klotho protein on the voltage gated K+ channel Kv1.3. Methods: cRNA encoding Kv1.3 (KCNA3) was injected into Xenopus oocytes and depolarization induced outward current in Kv1.3 expressing Xenopus oocytes determined utilizing dual electrode voltage clamp. Experiments were performed without or with prior treatment with recombinant human Klotho protein (50 ng/ml, 24 hours) in the absence or presence of a β-glucuronidase inhibitor D-saccharic acid-1,4-lactone (DSAL, 10 µM). Moreover, the voltage gated K+ current was determined in Jcam lymphoma cells by whole cell patch clamp following 24 hours incubation without or with recombinant human Klotho protein (50 ng/ml, 24 hours). Kv1.3 protein abundance in Jcam cells was determined utilising fluorescent antibodies in flow cytometry. Results: In Kv1.3 expressing Xenopus oocytes the Kv1.3 currents and the protein abundance of Kv1.3 were both significantly enhanced after treatment with recombinant human Klotho protein (50 ng/ml, 24 hours), an effect reversed by presence of DSAL. Moreover, treatment with recombinant human Klotho protein increased Kv currents and Kv1.3 protein abundance in Jcam cells. Conclusion: Alpha Klotho protein enhances Kv1.3 channel abundance and Kv1.3 currents in the plasma membrane, an effect depending on its β-glucuronidase activity. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2014
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49. Upregulation of the large conductance voltage- and Ca2+-activated K+ channels by Janus kinase 2.

Author

Hosseinzadeh, Zohreh, Almilaji, Ahmad, Honisch, Sabina, Pakladok, Tatsiana, GuoXing Liu, Bhavsar, Shefalee K., Ruth, Peter, Shumilina, Ekaterina, and Florian Lang

Subjects
HYPERPOLARIZATION (Cytology), CALCIUM channels, PROTEIN-tyrosine kinases, POTASSIUM channels, ION transport (Biology), CELL membranes, RHABDOMYOSARCOMA
Abstract

The iberiotoxin-sensitive large conductance voltage- and Ca2+-activated potassium (BK) channels (maxi-K+-channels) hyperpolarize the cell membrane thus supporting Ca2+ entry through Ca2+-release activated Ca2+ channels. Janus kinase-2 (JAK2) has been identified as novel regulator of ion transport. To explore whether JAK2 participates in the regulation of BK channels, cRNA encoding Ca2+-insensitive BK channels (BKM513I+Β899-903) was injected into Xenopus oocytes with or without cRNA encoding wild-type JAK2, gain-of-function V617FJAK2, or inactive K882EJAK2. K+ conductance was determined by dual electrode voltage clamp and BK-channel protein abundance by confocal microscopy. In A204 alveolar rhabdomyosarcoma cells, iberiotoxin-sensitive K+ current was determined utilizing whole cell patch clamp. A204 cells were further transfected with JAK2 and BK-channel transcript, and protein abundance was quantified by RT-PCR and Western blotting, respectively. As a result, the K+ current in BKM513I+Β899-903-expressing oocytes was significantly increased following coexpression of JAK2 or V617FJAK2 but not K882EJAK2. Coexpression of the BK channel with V617FJAK2 but not K882EJAK2 enhanced BK-channel protein abundance in the oocyte cell membrane. Exposure of BK-channel and V617FJAK2-expressing oocytes to the JAK2 inhibitor AG490 (40 ΔM) significantly decreased K+ current. Inhibition of channel insertion by brefeldin A (5 ΔM) decreased the K+ current to a similar extent in oocytes expressing the BK channel alone and in oocytes expressing the BK channel and V617FJAK2. The iberiotoxin (50 nM)-sensitive K+ current in rhabdomyosarcoma cells was significantly decreased by AG490 pretreatment (40 ΔM, 12 h). Moreover, overexpression of JAK2 in A204 cells significantly enhanced BK channel mRNA and protein abundance. In conclusion, JAK2 upregulates BK channels by increasing channel protein abundance in the cell membrane. [ABSTRACT FROM AUTHOR]

Published
2014
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50. Membrane androgen receptor sensitive Na+/H+ exchanger activity in prostate cancer cells.

Author

Chatterjee, Soumya, Schmidt, Sebastian, Pouli, Stella, Honisch, Sabina, Alkahtani, Saad, Stournaras, Christos, and Lang, Florian

Subjects
ANDROGEN receptors, SODIUM ions, PROSTATE cancer, CANCER cells, ENZYME activation, PH effect, GLUCOCORTICOIDS, PROTEIN kinases
Abstract

Highlights: [•] In prostate cancer cells membrane androgen receptor (mAR) activation increases pH. [•] mAR activation upregulates cariporide sensitive Na+/H+ exchanger (NHE). [•] The effect of mAR on pH and NHE requires serum & glucocorticoid inducible kinase. [•] The effect of mAR on pH and NHE requires Rho-associated protein kinase. [Copyright &y& Elsevier]

Published
2014
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