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2. CLC Anion/Proton Exchangers Regulate Secretory Vesicle Filling and Granule Exocytosis in Chromaffin Cells

Author

Comini, M, Sierra-Marquez, J, Guzman, G, Franzen, A, Willuweit, A, Katona, I, Hidalgo, P, Fahlke, C, and Guzman, RE

Subjects
Mammals, Mice, Knockout, Mice, Catecholamines, Chlorides, Chromaffin Cells, Secretory Vesicles, General Neuroscience, Animals, ddc:610, Protons, Exocytosis, Research Articles
Abstract

ClC-3, ClC-4, and ClC-5 are electrogenic chloride/proton exchangers that can be found in endosomal compartments of mammalian cells. Although the association with genetic diseases and the severe phenotype of knock-out animals illustrate their physiological importance, the cellular functions of these proteins have remained insufficiently understood. We here study the role of twoClcn3splice variants, ClC-3b and ClC-3c, in granular exocytosis and catecholamine accumulation of adrenal chromaffin cells using a combination of high-resolution capacitance measurements, amperometry, protein expression/gene knock out/down, rescue experiments, and confocal microscopy. We demonstrate that ClC-3c resides in immature as well as in mature secretory granules, where it regulates catecholamine accumulation and contributes to the establishment of the readily releasable pool of secretory vesicles. The lysosomal splice variant ClC-3b contributes to vesicle priming only with low efficiency and leaves the vesicular catecholamine content unaltered. The related Cl−/H+antiporter ClC-5 undergoes age-dependent downregulation in wild-type conditions. Its upregulation inClcn3−/−cells partially rescues the exocytotic mutant defect. Our study demonstrates how different CLC transporters with similar transport functions, but distinct localizations can contribute to vesicle functions in the regulated secretory pathway of granule secretion in chromaffin cells.SIGNIFICANCE STATEMENTCl−/H+exchangers are expressed along the endosomal/lysosomal system of mammalian cells; however, their exact subcellular functions have remained insufficiently understood. We used chromaffin cells, a system extensively used to understand presynaptic mechanisms of synaptic transmission, to define the role of CLC exchangers in neurosecretion. Disruption of ClC-3 impairs catecholamine accumulation and secretory vesicle priming. There are multiple ClC-3 splice variants, and only expression of one, ClC-3c, in double Cl−/H+exchanger-deficient cells fully rescues the WT phenotype. Another splice variant, ClC-3b, is present in lysosomes and is not necessary for catecholamine secretion. The distinct functions of ClC-3c and ClC-3b illustrate the impact of expressing multiple CLC transporters with similar transport functions and separate localizations in different endosomal compartments.

Published
2022
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23. DO SOBER EYEWITNESSES OUTPERFORM ALCOHOL INTOXICATED EYEWITNESSES IN A LINEUP?

Author

Angelica Hagsand, Roos-Af-Hjelmsäter, E., Granhag, P. A., Fahlke, C., and Söderpalm-Gordh, A.

Subjects
person identification, alcohol intoxicated, memoria de testigos, lineup, alcohol myopia theory, lcsh:BF1-990, identificación de personas, eyewitness memory, teoría de la miopía por alcohol, rueda de identificación, lcsh:Psychology, lcsh:Criminal law and procedure, lcsh:K5000-5582, intoxicación alcohólica
Abstract

Although alcohol intoxicated eyewitnesses are common, there are only a few studies in the area. The aim of the current study is to investigate how different doses of alcohol affect eyewitness lineup identification performance. The participants (N= 123) were randomly assigned to a 3 [Beverage: control (0.0 g/kg ethanol) vs. lower (0.4 g/kg ethanol) vs. higher alcohol dose (0.7 g/kg ethanol)] X 2 (Lineup: target-present vs. target-absent) between-subject design. Participants consumed two glasses of beverage at an even pace for 15 minutes. Five minutes after consumption the participants witnessed a film depicting a staged kidnapping. Seven days later, the participants returned to the laboratory and were asked to identify the culprit in a simultaneous lineup. The result showed that overall, the participants performed better than chance; however, their lineup performance was poor. There were no significant effects of alcohol intoxication with respect to performance, neither in target-present nor target-absent lineups. The study's results suggest that eyewitnesses who have consumed a lower (0.4 g/kg ethanol) or a higher (0.7 g/kg ethanol) dose of alcohol perform at the same level as sober eyewitnesses in a lineup. The results are discussed in relation to the alcohol myopia theory and suggestions for future research are made. Aunque los testigos presenciales con intoxicación alcohólica son frecuentes, sólo contamos con unos pocos estudios en esta área. El objetivo del presente estudio fue investigar cómo diferentes dosis de alcohol afectan la ejecución del testigo presencial en una rueda de identificación. Los participantes (N= 123) fueron asignados al azar a una de las condiciones de un diseño inter-sujetos 3 [Ingesta de alcohol: grupo control (0.0 g/kg etanol) vs. una dosis pequeña de alcohol (0.4 g/kg etanol) vs. una alta (0.7 g/kg etanol)] X 2 (Rueda de identificación: sospechoso presente vs. sospechoso ausente). Cinco minutos después de la ingesta, los participantes vieron una película que versaba sobre un secuestro. Siete días después, los participantes volvieron al laboratorio y se les pidió que identificaran al culpable en una rueda de identificación en formato de presentación simultáneo. Aunque la tasa de identificación era realmente pobre, los resultados mostraron que, en general, los testigos identificaban por encima al azar. No se encontró un efecto significativo del alcohol en la ejecución, tanto en ruedas como con el sospechoso presente como ausente. Estos resultados sugieren que los testigos presenciales que han consumido una tasa baja (0.4 g/kg etanol) o alta (0.7 g/kg etanol) de alcohol rinden al mismo nivel en una rueda de identificación que testigos sobrios. Se discuten los resultados en relación con la teoría de la miopía del alcohol y se sugieren futuras líneas de investigación.

Published
2013

24. Somatic effects of AAS abuse : A 30-years follow-up study of male former power sports athletes

Author

Bagge, A. S. Lindqvist, Rosen, T., Fahlke, C., Ehrnborg, C., Eriksson, B. O., Moberg, T., Thiblin, Ingemar, Bagge, A. S. Lindqvist, Rosen, T., Fahlke, C., Ehrnborg, C., Eriksson, B. O., Moberg, T., and Thiblin, Ingemar

Abstract

Objectives The aim of the present study was to investigate the association between somatic health and former abuse of AAS in former elite male athletes 30 years after the end of their active sports career. Design Retrospective follow-up study. Methods N = 996 former elite male athletes were sent a questionnaire concerning sociodemographic variables, previous and past sport activity and lifetime prevalence of seeking professional help for health problems. N = 683 (68.6%) answered the questionnaire. The lifetime prevalence of AAS-abuse was 21% (n = 143), while 79% (n = 540) did not admit having ever used AAS. Results Former AAS-abuse was associated with tendon ruptures (p = 0.01), depression (p = 0.001), anxiety (p = 0.01) and lower prevalence of prostate hypertrophy (p = 0.01) and decreased libido (p = 0.01). Former advanced AAS-abusers had higher anxiety (p = 0.004) compared to the former less advanced AAS-abusers. Moreover, former advanced AAS-abusers, compared to AAS-naïves, reported more psychiatric problems (p = 0.002), depression (p = 0.003) and anxiety (p = 0.00). Conclusions A former AAS-abuse seems to be associated with some somatic and mental health problem, although a former less advanced AAS-abuse is related to lower incidence of prostate hypertrophy. The results raise the question whether some of these associations might be dose- and frequency dependent. These findings should however be seen as hypothesis generating and further studies are needed.

Published
2017
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25. Myotonia congenita in the dog

Author

Giger, U., Gracis, M., George, A.L. Jr., Rhodes, T.H., Fahlke, C., Rajpurohit, Y., Bhalerao, D.P., Melniczek, J., Volk, S.W., Patterson, D.F., and Vite, C.H.

Subjects
Genetic research -- Analysis, Human genetics -- Research, Myotonia congenita -- Genetic aspects, Biological sciences
Published
2000

26. Minimization of childhood maltreatment is common and consequential : Results from a large, multinational sample using the Childhood Trauma Questionnaire

Author

MacDonald, K., Thomas, M. L., Sciolla, A. F., Schneider, B., Pappas, K., Bleijenberg, G., Bohus, M., Bekh, B., Carpenter, L., Carr, A., Dannlowski, U., Dorahy, M., Fahlke, C., Finzi-Dottan, R., Karu, T., Gerdner, Arne, Glaesmer, H., Grabe, H. J., Heins, M., Kenny, D. T., Kim, D., Knoop, H., Lobbestael, J., Lochner, C., Lauritzen, G., Ravndal, E., Riggs, S., Sar, V., Schäfer, I., Schlosser, N., Schwandt, M. L., Stein, M. B., Subic-Wrana, C., Vogel, M., Wingenfeld, K., MacDonald, K., Thomas, M. L., Sciolla, A. F., Schneider, B., Pappas, K., Bleijenberg, G., Bohus, M., Bekh, B., Carpenter, L., Carr, A., Dannlowski, U., Dorahy, M., Fahlke, C., Finzi-Dottan, R., Karu, T., Gerdner, Arne, Glaesmer, H., Grabe, H. J., Heins, M., Kenny, D. T., Kim, D., Knoop, H., Lobbestael, J., Lochner, C., Lauritzen, G., Ravndal, E., Riggs, S., Sar, V., Schäfer, I., Schlosser, N., Schwandt, M. L., Stein, M. B., Subic-Wrana, C., Vogel, M., and Wingenfeld, K.

Abstract

Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale-originally designed to assess a positive response bias-are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ's MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ's discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias-as detected by the MD subscale-has a small but significant moderating effect on the CTQ's discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables. © 2016 MacDonald et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author a, Running title: Minimizing Matters: The Childhood Trauma Questionnaire

Published
2016
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27. Minimization of Childhood Maltreatment Is Common and Consequential: Results from a Large, Multinational Sample Using the Childhood Trauma Questionnaire

Author

Macdonald, K, Thomas, M.L., Sciolla, A.F., Schneider, B., Pappas, K., Bleijenberg, G., Bohus, M., Bekh, B., Carpenter, L., Carr, A., Dannlowski, U., Dorahy, M., Fahlke, C., Finzi-Dottan, R., Karu, T., Gerdner, A., Glaesmer, H., Grabe, H.J., Heins, M., Kenny, D.T., Kim, D., Knoop, H., Lobbestael, J., Lochner, C., Lauritzen, G., Ravndal, E., Riggs, S., Sar, V., Schafer, I., Schlosser, N., Schwandt, M.L., Stein, M.B., Subic-Wrana, C., Vogel, M., Wingenfeld, K., Macdonald, K, Thomas, M.L., Sciolla, A.F., Schneider, B., Pappas, K., Bleijenberg, G., Bohus, M., Bekh, B., Carpenter, L., Carr, A., Dannlowski, U., Dorahy, M., Fahlke, C., Finzi-Dottan, R., Karu, T., Gerdner, A., Glaesmer, H., Grabe, H.J., Heins, M., Kenny, D.T., Kim, D., Knoop, H., Lobbestael, J., Lochner, C., Lauritzen, G., Ravndal, E., Riggs, S., Sar, V., Schafer, I., Schlosser, N., Schwandt, M.L., Stein, M.B., Subic-Wrana, C., Vogel, M., and Wingenfeld, K.

Abstract

Contains fulltext : 167949.PDF (publisher's version ) (Open Access), Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale-originally designed to assess a positive response bias-are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ's MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ's discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias-as detected by the MD subscale-has a small but significant moderating effect on the CTQ's discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables.

Published
2016

28. Minimization of childhood maltreatment is common and consequential: results from a large, multinational sample using the childhood trauma questionnaire

Author

Şar, Vedat (ORCID 0000-0002-5392-9644 & YÖK ID 8542), MacDonald, K.; Thomas, M.; Sciolla, A.; Schneider, B.; Pappas, K.; Bleijenberg, G.; Bohus, M.; Bekh, B.; Carpenter, L.; Carr, A.; Dannlowski, U.; Dorahy, M.; Fahlke, C.; Finzi-Dottan, R.; Karu, T.; Gerdner, A.; Glaesmer, H.; Grabe,H.J.; Heins, M.; Kenny, D., School of Medicine, Psychiatry, Şar, Vedat (ORCID 0000-0002-5392-9644 & YÖK ID 8542), MacDonald, K.; Thomas, M.; Sciolla, A.; Schneider, B.; Pappas, K.; Bleijenberg, G.; Bohus, M.; Bekh, B.; Carpenter, L.; Carr, A.; Dannlowski, U.; Dorahy, M.; Fahlke, C.; Finzi-Dottan, R.; Karu, T.; Gerdner, A.; Glaesmer, H.; Grabe,H.J.; Heins, M.; Kenny, D., School of Medicine, and Psychiatry

Abstract

Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale-originally designed to assess a positive response bias-are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ's MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ's discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias-as detected by the MD subscale-has a small but significant moderating effect on the CTQ's discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables., National Institutes Health; Australia Research Council; New South Wales Department of Juvenile Justice, Australia

Published
2016

30. The Concise Guide to PHARMACOLOGY 2013/14: overview

Author

Alexander, SP, Benson, HE, Faccenda, E, Pawson, AJ, Sharman, JL, McGrath, JC, Catterall, WA, Spedding, M, Peters, JA, Harmar, AJ, CGTP Collaborators, Abul-Hasn, N, Anderson, CM, Araiksinen, MS, Arita, M, Arthofer, E, Barker, EL, Barratt, C, Barnes, NM, Bathgate, R, Beart, PM, Belelli, D, Bennett, AJ, Birdsall, NJ, Boison, D, Bonner, TI, Brailsford, L, Bröer, S, Brown, P, Calo, G, Carter, WG, Chan, SL, Chao, MV, Chiang, N, Christopoulos, A, Chun, JJ, Cidlowski, J, Clapham, DE, Cockcroft, S, Connor, MA, Cox, HM, Cuthbert, A, Dautzenberg, FM, Davenport, AP, Dawson, PA, Dent, G, Dijksterhuis, JP, Dollery, CT, Dolphin, AC, Donowitz, M, Dubocovich, ML, Eiden, L, Eidne, K, Evans, BA, Fabbro, D, Fahlke, C, Farndale, R, Fitzgerald, GA, Fong, TM, Fowler, CJ, Fry, JR, Funk, CD, Futerman, AH, Ganapathy, V, Gaisnier, B, Gershengorn, MA, Goldin, A, Goldman, ID, Gundlach, AL, Hagenbuch, B, Hales, TG, Hammond, JR, Hamon, M, Hancox, JC, Hauger, RL, Hay, DL, Hobbs, AJ, Hollenberg, MD, Holliday, ND, Hoyer, D, Hynes, NA, Inui, KI, Ishii, S, Jacobson, KA, Jarvis, GE, Jarvis, MF, Jensen, R, Jones, CE, Jones, RL, Kaibuchi, K, Kanai, Y, Kennedy, C, Kerr, ID, Khan, AA, Klienz, MJ, Kukkonen, JP, Lapoint, JY, Leurs, R, Lingueglia, E, Lippiat, J, Lolait, SJ, Lummis, SC, Lynch, JW, MacEwan, D, Maguire, JJ, Marshall, IL, May, JM, McArdle, CA, Michel, MC, Millar, NS, Miller, LJ, Mitolo, V, Monk, PN, Moore, PK, Moorhouse, AJ, Mouillac, B, Murphy, PM, Neubig, RR, Neumaier, J, Niesler, B, Obaidat, A, Offermanns, S, Ohlstein, E, Panaro, MA, Parsons, S, Pwrtwee, RG, Petersen, J, Pin, JP, Poyner, DR, Prigent, S, Prossnitz, ER, Pyne, NJ, Pyne, S, Quigley, JG, Ramachandran, R, Richelson, EL, Roberts, RE, Roskoski, R, Ross, RA, Roth, M, Rudnick, G, Ryan, RM, Said, SI, Schild, L, Sanger, GJ, Scholich, K, Schousboe, A, Schulte, G, Schulz, S, Serhan, CN, Sexton, PM, Sibley, DR, Siegel, JM, Singh, G, Sitsapesan, R, Smart, TG, Smith, DM, Soga, T, Stahl, A, Stewart, G, Stoddart, LA, Summers, RJ, Thorens, B, Thwaites, DT, Toll, L, Traynor, JR, Usdin, TB, Vandenberg, RJ, Villalon, C, Vore, M, Waldman, SA, Ward, DT, Willars, GB, Wonnacott, SJ, Wright, E, Ye, RD, Yonezawa, A, and Zimmermann, M

Abstract

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Published
2013

37. FREE ORAL COMMUNICATIONS 4: ALCOHOL DEPENDENCE: TREATMENT APPROACHES * O4.1 * EFFECTIVENESS OF STIMULANT MEDICATION IN FETAL ALCOHOL SPECTRUM DISORDERS

Author

Infante, M. A., primary, Humber, C. C., additional, Mattson, S. N., additional, Riley, E. P., additional, Bryan, A. D., additional, Ewing, S. F., additional, Brock, A., additional, Magnan, R., additional, Hutchison, K., additional, Berglund, K. J., additional, Fahlke, C., additional, Berggren, U., additional, Zetterberg, H., additional, Blennow, K., additional, Engel, J., additional, Balldin, J., additional, Ulmer, A., additional, Lehert, P., additional, Mason, B., additional, Beaunieux, H., additional, Cauvin, C., additional, Lannuzel, C., additional, Duval, C., additional, Le Berre, A., additional, Vabret, F., additional, Pitel, A., additional, Allain, P., additional, Desgranges, B., additional, and Eustache, F., additional

Published
2011
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