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192 results on '"Eriksen, Jacob"'

1. Adaptor protein-3 produces synaptic vesicles that release phasic dopamine

Author

Jain, Shweta, Yee, Andrew G, Maas, James, Gierok, Sarah, Xu, Hongfei, Stansil, Jasmine, Eriksen, Jacob, Nelson, Alexandra B, Silm, Katlin, Ford, Christopher P, and Edwards, Robert H

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biological Psychology, Information and Computing Sciences, Psychology, Machine Learning, Mental Health, Behavioral and Social Science, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, Neurological, adaptor protein-3, phasic dopamine, reinforcement learning, synaptic vesicles, vesicular monoamine transporter 2
Abstract

The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.

Published
2023

2. Substrate recognition and proton coupling by a bacterial member of solute carrier family 17

Author

Batarni, Samir, Nayak, Nanda, Chang, Audrey, Li, Fei, Hareendranath, Surabhi, Zhou, Lexi, Xu, Hongfei, Stroud, Robert, Eriksen, Jacob, and Edwards, Robert H

Subjects
Biochemistry and Cell Biology, Medical Physiology, Biomedical and Clinical Sciences, Biological Sciences, Anions, Biological Transport, Escherichia coli, Escherichia coli Proteins, Mutation, Protons, Symporters, bacterial galactonate transport, proton coupling, solute carrier family (SLC) 17, vesicular glutamate transport, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

The solute carrier 17 family transports diverse organic anions using two distinct modes of coupling to a source of energy. Transporters that package glutamate and nucleotide into secretory vesicles for regulated release by exocytosis are driven by membrane potential but subject to allosteric regulation by H+ and Cl-. Other solute carrier 17 members including the lysosomal sialic acid exporter couple the flux of organic anion to cotransport of H+. To begin to understand how similar proteins can perform such different functions, we have studied Escherichia coli DgoT, a H+/galactonate cotransporter. A recent structure of DgoT showed many residues contacting D-galactonate, and we now find that they do not tolerate even conservative substitutions. In contrast, the closely related lysosomal H+/sialic acid cotransporter Sialin tolerates similar mutations, consistent with its recognition of diverse substrates with relatively low affinity. We also find that despite coupling to H+, DgoT transports more rapidly but with lower apparent affinity at high pH. Indeed, membrane potential can drive uptake, indicating electrogenic transport and suggesting a H+:galactonate stoichiometry >1. Located in a polar pocket of the N-terminal helical bundle, Asp46 and Glu133 are each required for net flux by DgoT, but the E133Q mutant exhibits robust exchange activity and rescues exchange by D46N, suggesting that these two residues operate in series to translocate protons. E133Q also shifts the pH sensitivity of exchange by DgoT, supporting a central role for the highly conserved TM4 glutamate in H+ coupling by DgoT.

Published
2023

3. Diversity of function and mechanism in a family of organic anion transporters

Author

Li, Fei, Eriksen, Jacob, Finer-Moore, Janet, Stroud, Robert M, and Edwards, Robert H

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, 1.1 Normal biological development and functioning, Animals, Escherichia coli, Glutamic Acid, Membrane Transport Proteins, Organic Anion Transporters, Rats, Substrate Specificity, Synaptic Vesicles, Medicinal and Biomolecular Chemistry, Biophysics, Biochemistry and cell biology
Abstract

Originally identified as transporters for inorganic phosphate, solute carrier 17 (SLC17) family proteins subserve diverse physiological roles. The vesicular glutamate transporters (VGLUTs) package the principal excitatory neurotransmitter glutamate into synaptic vesicles (SVs). In contrast, the closely related sialic acid transporter sialin mediates the flux of sialic acid in the opposite direction, from lysosomes to the cytoplasm. The two proteins couple in different ways to the H+ electrochemical gradient driving force, and high-resolution structures of the Escherichia coli homolog d-galactonate transporter (DgoT) and more recently rat VGLUT2 now begin to suggest the mechanisms involved as well as the basis for substrate specificity.

Published
2022

5. Allosteric Inhibition of a Vesicular Glutamate Transporter by an Isoform-Specific Antibody

Author

Eriksen, Jacob, Li, Fei, Stroud, Robert M, and Edwards, Robert H

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Biotechnology, Allosteric Regulation, Animals, Antibodies, Monoclonal, Chlorides, Epitopes, Glutamic Acid, HEK293 Cells, Humans, Protein Isoforms, Vesicular Glutamate Transport Protein 1, Vesicular Glutamate Transport Protein 2, Vesicular Glutamate Transport Proteins, Xenopus laevis, Medicinal and Biomolecular Chemistry, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Medicinal and biomolecular chemistry
Abstract

The role of glutamate in excitatory neurotransmission depends on its transport into synaptic vesicles by the vesicular glutamate transporters (VGLUTs). The three VGLUT isoforms exhibit a complementary distribution in the nervous system, and the knockout of each produces severe, pleiotropic neurological effects. However, the available pharmacology lacks sensitivity and specificity, limiting the analysis of both transport mechanism and physiological role. To develop new molecular probes for the VGLUTs, we raised six mouse monoclonal antibodies to VGLUT2. All six bind to a structured region of VGLUT2, five to the luminal face, and one to the cytosolic. Two are specific to VGLUT2, whereas the other four bind to both VGLUT1 and 2; none detect VGLUT3. Antibody 8E11 recognizes an epitope spanning the three extracellular loops in the C-domain that explains the recognition of both VGLUT1 and 2 but not VGLUT3. 8E11 also inhibits both glutamate transport and the VGLUT-associated chloride conductance. Since the antibody binds outside the substrate recognition site, it acts allosterically to inhibit function, presumably by restricting conformational changes. The isoform specificity also shows that allosteric inhibition provides a mechanism to distinguish between closely related transporters.

Published
2021

6. The mechanism and regulation of vesicular glutamate transport: Coordination with the synaptic vesicle cycle

Author

Eriksen, Jacob, Li, Fei, and Edwards, Robert H

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, 1.1 Normal biological development and functioning, Allosteric Regulation, Animals, Biological Transport, Chlorides, Glutamic Acid, Ligands, Substrate Specificity, Synaptic Vesicles, Vesicular Glutamate Transport Proteins, Allosteric regulation, Chloride conductance, Solute carrier (SLC) 17 family, Synaptic vesicle, Vesicular glutamate transport, Other Biological Sciences, Chemical Engineering, Biochemistry & Molecular Biology, Biophysics, Biochemistry and cell biology
Abstract

The transport of classical neurotransmitters into synaptic vesicles generally relies on a H+ electrochemical gradient (∆μH+). Synaptic vesicle uptake of glutamate depends primarily on the electrical component ∆ψ as the driving force, rather than the chemical component ∆pH. However, the vesicular glutamate transporters (VGLUTs) belong to the solute carrier 17 (SLC17) family, which includes closely related members that function as H+ cotransporters. Recent work has also shown that the VGLUTs undergo allosteric regulation by H+ and Cl-, and exhibit an associated Cl- conductance. These properties appear to coordinate VGLUT activity with the large ionic shifts that accompany the rapid recycling of synaptic vesicles driven by neural activity. Recent structural information also suggests common mechanisms that underlie the apparently divergent function of SLC17 family members, and that confer allosteric regulation.

Published
2020

7. Ion transport and regulation in a synaptic vesicle glutamate transporter

Author

Li, Fei, Eriksen, Jacob, Finer-Moore, Janet, Chang, Roger, Nguyen, Phuong, Bowen, Alisa, Myasnikov, Alexander, Yu, Zanlin, Bulkley, David, Cheng, Yifan, Edwards, Robert H, and Stroud, Robert M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, 1.1 Normal biological development and functioning, Allosteric Regulation, Amino Acid Sequence, Animals, Binding Sites, Chloride Channels, Chlorides, Cryoelectron Microscopy, Glutamic Acid, Hydrogen-Ion Concentration, Ion Transport, Membrane Potentials, Protein Domains, Rats, Synaptic Vesicles, Vesicular Glutamate Transport Protein 2, General Science & Technology
Abstract

Synaptic vesicles accumulate neurotransmitters, enabling the quantal release by exocytosis that underlies synaptic transmission. Specific neurotransmitter transporters are responsible for this activity and therefore are essential for brain function. The vesicular glutamate transporters (VGLUTs) concentrate the principal excitatory neurotransmitter glutamate into synaptic vesicles, driven by membrane potential. However, the mechanism by which they do so remains poorly understood owing to a lack of structural information. We report the cryo-electron microscopy structure of rat VGLUT2 at 3.8-angstrom resolution and propose structure-based mechanisms for substrate recognition and allosteric activation by low pH and chloride. A potential permeation pathway for chloride intersects with the glutamate binding site. These results demonstrate how the activity of VGLUTs can be coordinated with large shifts in proton and chloride concentrations during the synaptic vesicle cycle to ensure normal synaptic transmission.

Published
2020

8. Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort

Author

Greijdanus, Nynke G., Wienholts, Kiedo, Ubels, Sander, Talboom, Kevin, Hannink, Gerjon, Wolthuis, Albert, de Lacy, Francisco B., Lefevre, Jérémie H., Solomon, Michael, Frasson, Matteo, Rotholtz, Nicolas, Denost, Quentin, Perez, Rodrigo O., Konishi, Tsuyoshi, Panis, Yves, Rutegård, Martin, Hompes, Roel, Rosman, Camiel, van Workum, Frans, Tanis, Pieter J., de Wilt, Johannes H.W., Bremers, Andreas J.A., Ferenschild, Floris T., de Vriendt, Stefanie, D’Hoore, André, Bislenghi, Gabriele, Farguell, Jordi, Lacy, Antonio M., Atienza, Paula González, van Kessel, Charlotte S., Parc, Yann, Voron, Thibault, Collard, Maxime K., Muriel, Jorge Sancho, Cholewa, Hannia, Mattioni, Laura A., Frontali, Alice, Polle, Sebastiaan W., Polat, Fatih, Obihara, Ndidi J., Vailati, Bruna B., Kusters, Miranda, Tuynmann, Jurriaan B., Hazen, Sanne J.A., Grüter, Alexander A.J., Amano, Takahiro, Fujiwara, Hajime, Salomon, Mario, Ruiz, Hernán, Gonzalez, Ricardo, Estefanía, Diego, Avellaneda, Nicolas, Carrie, Augusto, Santillan, Mateo, Pantoja Pachajoa, Diana A., Parodi, Matias, Gielis, Manuel, Binder, Alf-Dorian, Gürtler, Thomas, Riedl, Peter, Badiani, Sarit, Berney, Christophe, Morgan, Matthew, Hollington, Paul, da Silva, Nigel, Nair, Gavin, Ho, Yiu M., Lamparelli, Michael, Kapadia, Raj, Kroon, Hidde M., Dudi-Venkata, Nagendra N., Liu, Jianliang, Sammour, Tarik, Flamey, Nicolas, Pattyn, Paul, Chaoui, Ahmed, Vansteenbrugge, Louis, van den Broek, Nathalie E.J., Vanclooster, Patrick, de Gheldere, Charles, Pletinckx, Pieter, Defoort, Barbara, Dewulf, Maxime, Slavchev, Mihail, Belev, Nikolay, Atanasov, Boyko, Krastev, Panche, Sokolov, Manol, Maslyankov, Svilen, Gribnev, Petar, Pavlov, Vasil, Ivanov, Tsvetomir, Karamanliev, Martin, Filipov, Emil, Tonchev, Pencho, Aigner, Felix, Mitteregger, Martin, Allmer, Caterina, Seitinger, Gerald, Colucci, Nicola, Buchs, Nicolas, Ris, Frédéric, Toso, Christian, Gialamas, Eleftherios, Vuagniaux, Aurélie, Chautems, Roland, Sauvain, Marc-Olivier, Daester, Silvio, von Flüe, Markus, Guenin, Marc-Olivier, Taha-Mehlitz, Stephanie, Hess, Gabriel F., Martínek, Lubomír, Skrovina, Matej, Machackova, Maria, Benčurik, Vladimir, Uluk, Deniz, Pratschke, Johann, Dittrich, Luca S., Guel-Klein, Safak, Perez, Daniel, Grass, Julia-Kristin, Melling, Nathaniel, Mueller, Simone, Iversen, Lene H., Eriksen, Jacob D., Baatrup, Gunnar, Al-Najami, Issam, Bjørsum-Meyer, Thomas, Teras, Jüri, Teras, Roland M., Monib, Fatma A., Abu Elnga Ahmed, Nagm Eldin, Alkady, Eithar, Ali, Ahmed K., Khedr, Gehan Abd Elatti, Abdelaal, Ahmed Samir, Bassyouni Ashoush, Fouad M., Ewedah, Moataz, Elshennawy, Eslam M., Hussein, Mohamed, Fernández-Martínez, Daniel, García-Flórez, Luis J., Fernández-Hevia, María, Suárez-Sánchez, Aida, del Hoyo Aretxabala, Izaskun, Docampo, Iria Losada, Zabala, Jesús Gómez, Tejedor, Patricia, Morales Bernaldo de Quirós, Javier T., Quiroga, Ignacio Bodega, Navarro-Sánchez, Antonio, Darias, Iván Soto, Fernández, Cristina López, de La Cruz Cuadrado, Cristina, Sánchez-Guillén, Luis, López-Rodríguez-Arias, Francisco, Soler-Silva, Álvaro, Arroyo, Antonio, Bernal-Sprekelsen, Juan C., Gómez-Abril, Segundo Á., Gonzálvez, Paula, Torres, María T., Sánchez, Teresa Rubio, Antona, Francisco Blanco, Sánchez Lara, Juan E., Alcázar Montero, José A., Fernández-Martínez, Daniel, García-Flórez, Luis J., Fernández-Hevia, María, Suárez-Sánchez, Aida, Colás-Ruiz, Enrique, Tasende-Presedo, Marta M., Fernández-Hurtado, Ignacio, Cifuentes-Ródenas, José A., Suárez, Marta Castro, Losada, Manuel, Hernández, Miguel, Alonso, Alfredo, Diéguez, Beatriz, Serralta, Daniel, Medina Quintana, Rita E., Gil Lopez, Jose M., Pinto, Francisca Lima, Nieto-Moreno, Elena, Bonito, Alba Correa, Santacruz, Carlos Cerdán, Marcos, Elena Bermejo, Septiem, Javier García, Calero-Lillo, Aránzazu, Alanez-Saavedra, Javier, Muñoz-Collado, Salvador, López-Lara, Manuel, Martínez, María Labalde, Herrero, Eduardo Ferrero, Borda, Francisco Javier García, Villar, Óscar García, Escartín, Jorge, Blas, Juan L., Ferrer, Rocío, Egea, Jorge García, Rodríguez-Infante, Antonio, Mínguez-Ruiz, Germán, Carreño-Villarreal, Guillermo, Pire-Abaitua, Gerardo, Dziakova, Jana, Rodríguez, Carlos Sáez-Cazallas, Pizarro Aranda, María J., Muguerza Huguet, José M., Borda-Arrizabalaga, Nerea, Enriquez-Navascués, José M., Echaniz, Garazi Elorza, Ansorena, Yolanda Saralegui, Estaire-Gómez, Mercedes, Martínez-Pinedo, Carlos, Barbero-Valenzuela, Alejandro, Ruíz-García, Pablo, Kraft, Miquel, Gómez-Jurado, María J., Pellino, Gianluca, Espín-Basany, Eloy, Cotte, Eddy, Panel, Nathalie, Goutard, Claire-Angéline, deÁngelis, Nicola, Lauka, Lelde, Shaikh, Shafaque, Osborne, Laura, Ramsay, George, Nichita, Vladimir-Ion, Bhandari, Santosh, Sarmah, Panchali, Bethune, Rob M., Pringle, Heather C.M., Massey, Lisa, Fowler, George E., Hamid, Hytham K.S., de Simone, Belinda D., Kynaston, James, Bradley, Nicholas, Stienstra, Roxane M., Gurjar, Shashank, Mukherjee, Tanmoy, Chandio, Ashfaq, Ahmed, Safia, Singh, Baljit, Runau, Francois, Chaudhri, Sanjay, Siaw, Oliver, Sarveswaran, Janahan, Miu, Victor, Ashmore, Daniel, Darwich, Haitham, Singh-Ranger, Deepak, Singh, Nirbhaibir, Shaban, Mohamed, Gareb, Fahed, Petropolou, Thalia, Polydorou, Adreas, Dattani, Mit, Afzal, Asma, Bavikatte, Akshay, Sebastian, Boby, Ward, Nicholas, Mishra, Amitabh, Manatakis, Dimitrios, Agalianos, Christos, Tasis, Nikolaos, Antonopoulou, Maria-Ioanna, Karavokyros, Ioannis, Charalabopoulos, Alexandros, Schizas, Dimitrios, Baili, Efstratia, Syllaios, Athanasios, Karydakis, Lysandros, Vailas, Michail, Balalis, Dimitrios, Korkolis, Dimitrios, Plastiras, Aris, Rompou, Aliki, Xenaki, Sofia, Xynos, Evangelos, Chrysos, Emmanuel, Venianaki, Maria, Christodoulidis, Grigorios, Perivoliotis, Konstantinos, Tzovaras, George, Baloyiannis, Ioannis, Ho, Man-Fung, Ng, Simon Siu-man, Mak, Tony Wing-chung, Futaba, Kaori, Šantak, Goran, Šimleša, Damir, osić, Jurica, Zukanović, Goran, Kelly, Michael E., Larkin, John O., McCormick, Paul H., Mehigan, Brian J., Connelly, Tara M., Neary, Peter, Ryan, Jessica, McCullough, Peter, Al-Juaifari, Maytham A., Hammoodi, Hayder, Abbood, Ali Hashim, Calabrò, Marcello, Muratore, Andrea, Terra, Antonio La, Farnesi, Francesca, Feo, Carlo V., Fabbri, Nicolò, Pesce, Antonio, Fazzin, Marta, Roscio, Francesco, Clerici, Federico, Lucchi, Andrea, Vittori, Laura, Agostinelli, Laura, Ripoli, Maria Cristina, Sambucci, Daniele, Porta, Andrea, Sinibaldi, Giovanni, Crescentini, Giacomo, larcinese, Antonella, Picone, Emanuele, Persiani, Roberto, Biondi, Alberto, Pezzuto, Roberto, Lorenzon, Laura, Rizzo, Gianluca, Coco, Claudio, D’Agostino, Luca, Spinelli, Antonino, Sacchi, Matteo M., Carvello, Michele, Foppa, Caterina, Spinelli, Antonino, Sacchi, Matteo M., Carvello, Michele, Foppa, Caterina, Maroli, Annalisa, Palini, Gian M., Garulli, Gianluca, Zanini, Nicola, Delrio, Paolo, Rega, Daniela, Carbone, Fabio, Aversano, Alessia, Pirozzolo, Giovanni, Recordare, Alfonso, DʼAlimonte, Lucrezia, Vignotto, Chiara, Corbellini, Carlo, Sampietro, Gianluca M., Lorusso, Leonardo, Manzo, Carlo A., Ghignone, Federico, Ugolini, Giampaolo, Montroni, Isacco, Pasini, Franceso, Pasini, Francesco, Ballabio, Michele, Bisagni, Pietro, Armao, Francesca T., Longhi, Marco, Ghazouani, Omar, Galleano, Raffaele, Tamini, Nicolò, Oldani, Massimo, Nespoli, Luca, Picciariello, Arcangelo, Altomare, Donato F., Tomasicchio, Giovanni, Lantone, Giuliano, Catena, Fausto, Giuffrida, Mario, Annicchiarico, Alfredo, Perrone, Gennaro, Grossi, Ugo, Santoro, Giulio A., Zanus, Giacomo, Iacomino, Alessandro, Novello, Simone, Passuello, Nicola, Zucchella, Martino, Puca, Lucia, deGiuli, Maurizio, Reddavid, Rossella, Scabini, Stefano, Aprile, Alessandra, Soriero, Domenico, Fioravanti, Emanuela, Rottoli, Matteo, Romano, Angela, Tanzanu, Marta, Belvedere, Angela, Mariani, Nicolò M., Ceretti, Andrea P., Opocher, Enrico, Gallo, Gaetano, Sammarco, Giuseppe, de Paola, Gilda, Pucciarelli, Salvatore, Marchegiani, Francesco, Spolverato, Gaya, Buzzi, Gianluca, Di Saverio, Salomone, Meroni, Paola, Parise, Cristiano, Bottazzoli, Elisa I., Lapolla, Pierfrancesco, Brachini, Gioia, Cirillo, Bruno, Mingoli, Andrea, Sica, Giuseppe, Siragusa, Leandro, Bellato, Vittoria, Cerbo, Daniele, de Pasqual, Carlo A., de Manzoni, Giovanni, di Cosmo, Maria A., Alrayes, Bourhan M.H., Qandeel, Mahmoud W. M., Hani, Mohammad Bani, Rabadi, Alexander, el Muhtaseb, Mohammad S., Abdeen, Basel, Karmi, Fahed, Žilinskas, Justas, Latkauskas, Tadas, Tamelis, Algimantas, Pikūnienė, Ingrida, Šlenfuktas, Vygintas, Poskus, Tomas, Kryzauskas, Marius, Jakubauskas, Matas, Mikalauskas, Saulius, Jakubauskiene, Lina, Hassan, Soha Y., Altrabulsi, Amani, Abdulwahed, Eman, Ghmagh, Reem, Deeknah, Abdulqudus, Alshareea, Entisar, Elhadi, Muhammed, Abujamra, Saleh, Msherghi, Ahmed A., Tababa, Osama W.E., Majbar, Mohammed A., Souadka, Amine, Benkabbou, Amine, Mohsine, Raouf, Echiguer, Sabrillah, Moctezuma-Velázquez, Paulina, Salgado-Nesme, Noel, Vergara-Fernández, Omar, Sainz-Hernández, Juan C., Alvarez-Bautista, Francisco E., Zakaria, Andee D., Zakaria, Zaidi, Wong, Michael P.K., Ismail, Razif, Ibrahim, Aini F., Abdullah, Nik A.N., Julaihi, Rokayah, Bhat, Sameer, OʼGrady, Greg, Bissett, Ian, Lamme, Bas, Musters, Gijsbert D., Dinaux, Anne M., Grotenhuis, Brechtje A., Steller Arend G.J. Aalbers, Ernst J., Leeuwenburgh, Marjolein M., Rutten, Harm J.T., Burger, Jacobus W.A., Bloemen, Johanne G., Ketelaers, Stijn H.J., Waqar, Usama, Chawla, Tabish, Rauf, Hareem, Rani, Pallavi, Talsma, Aaldert K., Scheurink, Lieke, van Praagh, Jasper B., Segelman, Josefin, Nygren, Jonas, Anderin, Kajsa, Tiefenthal, Marit, de Andrés, Beatriz, Beltrán de Heredia, Juan P., Vázquez, Andrea, Gómez, Tania, Golshani, Parisa, Kader, Rawaz, Mohamed, Abudi, Westerterp, Marinke, Marinelli, Andreas, Niemer, Quirine, Doornebosch, Pascal G., Shapiro, Joël, Vermaas, Maarten, de Graaf, Eelco J.R., van Westreenen, Hendrik L., Zwakman, Marije, van Dalsen, Annette D., Vles, Wouter J., Nonner, Joost, Toorenvliet, Boudewijn R., Janssen, Paul T.J., Verdaasdonk, Emiel G.G., Amelung, Femke J., Peeters Renu R. Bahadoer, Koen C.M.J., Holman, Fabian A., Heemskerk, Jeroen, Vosbeek, Noortje, Leijtens, Jeroen W.A., Taverne, Sophie B.M., Heijnen, Bob H.M., El-Massoudi, Youssef, de Groot-van Veen, Irene, Hoff, Christiaan, Jou-Valencia, Daniela, Consten, Esther C.J., Burghgraef, Thijs A., Geitenbeek, Ritch, Hulshof, Lorenzo G.W.L., Slooter, Gerrit D., Reudink, Muriël, Bouvy, Nicole D., Wildeboer, Aurelia C. L., Verstappen, Sonja, Pennings, Alexander J., van den Hengel, Berber, Wijma, Allard G., de Haan, Jael, de Nes, Lindsey C.F., Heesink, Vera, Karsten, Tom, Heidsma, Charlotte M., Koemans, Willem J., Dekker, Jan-Willem T., van der Zijden, Charlène J., Roos, Daphne, Demirkiran, Ahmet, van der Burg, Sjirk, Oosterling, Steven J., Hoogteijling, Tijs J., Wiering, Bastiaan, Smeeing, Diederik P.J., Havenga, Klaas, Lutfi, Hamid, Consten, Esther C.J., Tsimogiannis, Konstantinos, Sköldberg, Filip, Folkesson, Joakim, den Boer, Frank, van Schaik, Ted G., van Gerven, Pieter, Sietses, Colin, Hol, Jeroen C., Boerma, Evert-Jan G., Creemers, Davy M.J., Schultz, Johannes K., Frivold, Tone, Riis, Rolf, Gregussen, Hilde, Busund, Sondre, Sjo, Ole H., Gaard, Maria, Krohn, Nina, Ersryd, Amanda L., Leung, Edmund, Waqar, Usama, Chawla, Tabish, Rauf, Hareem, Rani, Pallavi, Sultan, Hytham, Hajjaj, Baraa Nabil, Alhisi, Ahmed Jehad, Khader, Ahmed A.E., Mendes, Ana Filipa Dias, Semião, Miguel, Faria, Luis Queiroz, Azevedo, Constança, da Costa Devesa, Helena M., Martins, Sónia Fortuna, Rodrigues Jarimba, Aldo M., Ribeiro Marques, Sónia M., Ferreira, Rita Marques, Oliveira, António, Ferreira, Cátia, Pereira, Ricardo, Surlin, Valeriu M., Graure, Giorgiana M., Ramboiu, Stefan Patrascu Sandu D., Negoi, Ionut, Ciubotaru, Cezar, Stoica, Bogdan, Tanase, Ioan, Stoica, Bogdan, Ciubotaru, Cezar, Negoita, Valentina M., Florea, Sabrina, Macau, Florin, Vasile, Mihai, Stefanescu, Victor, Dimofte, Gabriel-Mihail, Luncă, Sorinel, Roată, Cristian-Ene, Mu[Latin Small Letter s with comma below]ină, Ana-Maria, Garmanova, Tatiana, Agapov, Mikhail N., Markaryan, Daniil G., Eduard, Galliamov, Yanishev, Alexey, Abelevich, Alexander, Bazaev, Andrey, Rodimov, Sergey V., Filimonov, Victor B., Melnikov, Andrey A., Suchkov, Igor A., Drozdov, EvgeniyS., Kostromitskiy, Dmitriy N., Sjöström, Olle, Matthiessen, Peter, Baban, Bayar, Gadan, Soran, Jadid, Kaveh Dehlaghi, Staffan, Maria, Park, Jennifer M., Rydbeck, Daniel, Lydrup, Marie-Louise, Buchwald, Pamela, Jutesten, Henrik, Darlin, Lotten, Lindqvist, Ebba, Nilsson, Karl, Larsson, Per-Anders, Jangmalm, Staffan, Košir, Jurij A., Tomažič, Aleš, Grosek, Jan, Božič, Tajda Košir, Zazo, Aya, Zazo, Rama, Fares, Hala, Ayoub, Kusay, Niazi, Ammar, Mansour, Ali, Abbas, Ayman, Tantoura, Mohammad, Hamdan, Alaa, Hassan, Naya, Hasan, Bassam, Saad, Ahmad, Sebai, Amine, Haddad, Anis, Maghrebi, Houcine, Kacem, Montasser, Yalkın, Ömer, Samsa, Mehmet Veysi, Atak, İbrahim, Balci, Bengi, Haberal, Elifcan, Dogan, Lütfi, Gecim, Ibrahim E., Akyol, Cihangir, Koc, Mehmet A., Sivrikoz, Emre, Piyadeoğlu, Deniz, Larkin, John O., avanagh, Dara O., Sökmen, Selman, Bişgin, Tayfun, Günenç, Erşan, Güzel, Melek, Leventoğlu, Sezai, Yüksel, Osman, Kozan, Ramazan, Göbüt, Hüseyin, Cengiz, Fevzi, Erdinc, Kemal, Acar, Nihan Coşgun, Kamer, Erdinc, Özgür, İlker, Aydın, Oguzhan, Keskin, Metin, Bulut, Mehmet Türker, Kulle, Cemil B., Kara, Yasin, Sıbıç, Osman, Özata, İbrahim H., Buğra, Dursun, Balık, Emre, Kulle, Cemil B., Çakır, Murat, Alhardan, Anas, Colak, Elif, CiftciEngin Aybar, Ahmet B., Sari, Ahmet Can, Atici, Semra Demirli, Kaya, Tayfun, Dursun, Ayberk, Calik, Bulent, Özkan, Ömer Faruk, Ülgür, Hanife Şeyda, Düzgün, Özgül, Monson, John, George, Sarah, Woods, Kayla, Al-Eryani, Fatima, Albakry, Rudaina, Coetzee, Emile, Boutall, Adam, Herman, Ayesiga, Warden, Claire, Mugla, Naser, Forgan, Tim, Mia, Imraan, and Lambrechts, Anton

Published
2023
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9. Resting state structure of the hyperdepolarization activated two-pore channel 3

Author

Dickinson, Miles Sasha, Myasnikov, Alexander, Eriksen, Jacob, Poweleit, Nicole, and Stroud, Robert M

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurosciences, 1.1 Normal biological development and functioning, Action Potentials, Cryoelectron Microscopy, HEK293 Cells, Humans, Ion Channel Gating, Models, Molecular, Protein Conformation, Sodium, Voltage-Gated Sodium Channels, Zebrafish Proteins, ion channel, cryoEM, voltage sensors, structure, electrophysiology
Abstract

Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form the basis of all neuronal signaling. We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between -20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. The structure, confirmed by our electrophysiology, illustrates the configuration of a bona fide resting state voltage sensor, observed without the need for any inhibitory ligand, and independent of any chemical or mutagenic alteration.

Published
2020

10. Structures suggest a mechanism for energy coupling by a family of organic anion transporters.

Author

Leano, Jonathan B, Batarni, Samir, Eriksen, Jacob, Juge, Narinobu, Pak, John E, Kimura-Someya, Tomomi, Robles-Colmenares, Yaneth, Moriyama, Yoshinori, Stroud, Robert M, and Edwards, Robert H

Subjects
Escherichia coli, Protons, Sugar Acids, Escherichia coli Proteins, Organic Anion Transporters, Protein Conformation, Biological Transport, Energy Metabolism, Models, Molecular, Models, Molecular, Developmental Biology, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences
Abstract

Members of the solute carrier 17 (SLC17) family use divergent mechanisms to concentrate organic anions. Membrane potential drives uptake of the principal excitatory neurotransmitter glutamate into synaptic vesicles, whereas closely related proteins use proton cotransport to drive efflux from the lysosome. To delineate the divergent features of ionic coupling by the SLC17 family, we determined the structure of Escherichia coli D-galactonate/H+ symporter D-galactonate transporter (DgoT) in 2 states: one open to the cytoplasmic side and the other open to the periplasmic side with substrate bound. The structures suggest a mechanism that couples H+ flux to substrate recognition. A transition in the role of H+ from flux coupling to allostery may confer regulation by trafficking to and from the plasma membrane.

Published
2019

11. Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and Release Properties

Author

Silm, Kätlin, Yang, Jing, Marcott, Pamela F, Asensio, Cedric S, Eriksen, Jacob, Guthrie, Daryl A, Newman, Amy H, Ford, Christopher P, and Edwards, Robert H

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Mental Health, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Adaptor Protein Complex 3, Animals, Calcium Channels, Dopamine, Dopaminergic Neurons, Exocytosis, Glutamic Acid, Mesencephalon, Mice, Neurons, Neurotransmitter Agents, Synaptic Vesicles, AP-3, Ca++ channel coupling, VGLUT, VMAT, adaptor protein 3, dopamine, frequency dependence, glutamate, neurotransmitter corelease, release probability, synaptic vesicle, vesicular glutamate transporter, vesicular monoamoine transporter, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

In contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca2+ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals.

Published
2019

15. Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism

Author

Eriksen, Jacob, Chang, Roger, McGregor, Matt, Silm, Katlin, Suzuki, Toshiharu, and Edwards, Robert H

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Mental Health, Allosteric Regulation, Animals, Biological Transport, Glutamic Acid, Neurotransmitter Agents, Oocytes, Protons, Synaptic Transmission, Synaptic Vesicles, Vesicular Glutamate Transport Proteins, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

The quantal nature of synaptic transmission requires a mechanism to transport neurotransmitter into synaptic vesicles without promoting non-vesicular efflux across the plasma membrane. Indeed, the vesicular transport of most classical transmitters involves a mechanism of H(+) exchange, which restricts flux to acidic membranes such as synaptic vesicles. However, vesicular transport of the principal excitatory transmitter glutamate depends primarily on membrane potential, which would drive non-vesicular efflux, and the role of protons is unclear. Adapting electrophysiology to record currents associated with the vesicular glutamate transporters (VGLUTs), we characterize a chloride conductance that is gated by lumenal protons and chloride and supports glutamate uptake. Rather than coupling stoichiometrically to glutamate flux, lumenal protons and chloride allosterically activate vesicular glutamate transport. Gating by protons serves to inhibit what would otherwise be substantial non-vesicular glutamate efflux at the plasma membrane, thereby restricting VGLUT activity to synaptic vesicles.

Published
2016

21. Allosteric Regulation of a Synaptic Vesicle Glutamate Transporter

Author

Li, Fei, primary, Eriksen, Jacob, additional, Oses-Prieto, Juan A., additional, Gomez, Yessica K., additional, Xu, Hongfei, additional, Finer-Moore, Janet, additional, Nguyen, Phuong, additional, Bowen, Alisa, additional, Nelson, Andrew, additional, Burlingame, Alma, additional, Grabe, Michael, additional, Stroud, Robert M., additional, and Edwards, Robert H., additional

Published
2022
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23. Implementation of a standardized surgical technique and peri-operative care pathway in robot-assisted restorative rectal cancer resection. A single center cohort study

Author

Eriksen, Jacob Damgaard, primary, Thaysen, Henriette Vind, additional, Emmertsen, Katrine Jøssing, additional, Madsen, Anders Husted, additional, Tøttrup, Anders, additional, Nørager, Charlotte Buchard, additional, Ljungmann, Ken, additional, Thomassen, Niels, additional, Delaney, Conor P., additional, and Iversen, Lene Hjerrild, additional

Published
2022
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24. Additional file 1 of Implementation of a standardized surgical technique in robot-assisted restorative rectal cancer resection: a single center cohort study

Author

Eriksen, Jacob Damgaard, Thaysen, Henriette Vind, Emmertsen, Katrine Jøssing, Madsen, Anders Husted, Tøttrup, Anders, Nørager, Charlotte Buchard, Ljungmann, Ken, Thomassen, Niels, Delaney, Conor Patrick, and Iversen, Lene Hjerrild

Abstract

Additional file 1. A detailed description from Dr. Conor P. Delaney on how to perform a standardized restorative rectal resection.

Published
2022
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25. Additional file 2 of Implementation of a standardized surgical technique in robot-assisted restorative rectal cancer resection: a single center cohort study

Author

Eriksen, Jacob Damgaard, Thaysen, Henriette Vind, Emmertsen, Katrine Jøssing, Madsen, Anders Husted, Tøttrup, Anders, Nørager, Charlotte Buchard, Ljungmann, Ken, Thomassen, Niels, Delaney, Conor Patrick, and Iversen, Lene Hjerrild

Abstract

Additional file 2. The written form that the surgeons registered immediately after surgery. TME, total mesorectal excision; PME, partial mesorectal excision.

Published
2022
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33. FactCheckEU - Arguing for the truth: A study of the FactCheckEU media outlet's argumentations during the coverage of the 2019 European elections

Author

Eriksen, Jacob Christian and Bengtsson, Mette

Subjects
Parlamentet, Fakta, IFCN, Fact-Checking, Fact checking, faktatjekmedier, EP-valg, FactCheckEU, argumenter, faktatjek, argumentation, retorik, jounralistik, sandhed, EU, Europa, Fact Check, faktatjekjournalistik
Abstract

This Master’s thesis in journalism examines the use of argumentation in European fact-check journalism during the months leading up to the European Parliament elections of 2019. The research is focused on content and text analysis of the fact-checking articles published through the FactCheckEU cooperative platform that includes 19 European media outlets from 13 countries. The study analyzes the fact-checking productions through first a quantitative analysis and secondly a qualitative analysis of the 86 fact-checking articles that have been published from FactCheckEU.The study explores different argumentative approaches that fact-checkers employ when fact-checking a selected claim. The study identifies six primary approaches: a disqualifying approach, an authority-based approach, a deconstructive approach, a mediating approach, a detail-oriented approach and an opponent-free approach. The study finds that the media outlets of FactCheckEU are mostly focused on claims from politicians and social media sites. Quantitative analysis suggests that argumentative approaches differ based on the claimant’s type. Other possible factors that might influence the fact-checker’s chosen argumentative approach are also discussed, including questions of news value and trust. It is furthermore discussed how the findings of this study might affect the general understanding of the epistemology of fact-checking as well as the future of global fact-checking movement.

Published
2019

35. Ion transport and regulation in a synaptic vesicle glutamate transporter.

Author

Fei Li, Eriksen, Jacob, Finer-Moore, Janet, Chang, Roger, Phuong Nguyen, Bowen, Alisa, Myasnikov, Alexander, Zanlin Yu, Bulkley, David, Yifan Cheng, Edwards, Robert H., and Stroud, Robert M.

Subjects
*ION transport (Biology), *SYNAPTIC vesicles, *NEUROTRANSMITTERS, *NEURAL transmission, *NEURODEGENERATION
Abstract

Synaptic vesicles accumulate neurotransmitters, enabling the quantal release by exocytosis that underlies synaptic transmission. Specific neurotransmitter transporters are responsible for this activity and therefore are essential for brain function. The vesicular glutamate transporters (VGLUTs) concentrate the principal excitatory neurotransmitter glutamate into synaptic vesicles, driven by membrane potential. However, the mechanism by which they do so remains poorly understood owing to a lack of structural information. We report the cryo-electron microscopy structure of rat VGLUT2 at 3.8-angstrom resolution and propose structure-based mechanisms for substrate recognition and allosteric activation by low pH and chloride. A potential permeation pathway for chloride intersects with the glutamate binding site. These results demonstrate how the activity of VGLUTs can be coordinated with large shifts in proton and chloride concentrations during the synaptic vesicle cycle to ensure normal synaptic transmission. [ABSTRACT FROM AUTHOR]

Published
2020
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36. Diagnostic accuracy of ultrasound-guided core biopsy of peripheral nerve sheath tumors.

Author

Tøttrup, Mikkel, Eriksen, Jacob D., Hellfritzsch, Michel B., Sørensen, Flemming B., Baad‐Hansen, Thomas, and Baad-Hansen, Thomas

Abstract

Purpose: To retrospectively evaluate the diagnostic accuracy of and complications from ultrasound-guided core needle biopsy (UGCNB) of suspected peripheral nerve sheath tumors (PNSTs).Methods: Patients undergoing UGCNB from January 2004 to December 2016, based on the suspicion of PNST, were included in the study. Age, gender, anatomical location, dates of relevant events, and histopathological reports of the UGCNB cores and the resected tumors were retrieved from the patients' medical records.Results: A total of 154 UGCNBs were identified. One hundred and forty (90.9%) of these resulted in a conclusive histopathological report, while 14 were unsuited for histopathological analysis due to insufficient amount of tissue and/or nonrepresentative tissue. The overall diagnostic accuracy of UGCNB with respect to discriminate malignant from benign tumors was 99.3%, while correct specific UGCNB diagnoses were confirmed in 95.1% of the cases. Sensitivity and specificity were 90.9% (95% CI: 58.7-99.8%) and 100% (95% CI: 97.2-100%), respectively. The positive predictive value was 100%, and the negative predictive value was 99.2%. Except for one patient, who reported mild dysesthesia, which resolved 2 days after the UGCNB, no complications were reported.Conclusion: This study suggests that UGCNB is accurate and safe in patients suspected for PNST. [ABSTRACT FROM AUTHOR]

Published
2020
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39. Severe bleeding after sinus floor elevation using the transcrestal technique: a case report.

Author

Storgård Jensen, Simon, Eriksen, Jacob, and Schiødt, Morten

Subjects
ORAL surgery, DENTAL implant complications, MAXILLARY sinus surgery, ORAL hemorrhage, EDEMA, TOMOGRAPHY, ALVEOLAR process, ARTERIES
Abstract

Aim: To present a rare but clinically significant complication to sinus floor elevation (SFE) using the transcrestal technique. Materials and methods: Transcrestal SFE with simultaneous implant placement was performed in the maxillary right second premolar region of a healthy 70-year-old woman with no history of a bleeding disorder. Results: The patient reported to the emergency care unit a few hours after the surgery with ongoing bleeding and progressive swelling of especially the right side of the midface. The buccal swelling did not allow the patient to close her mouth and the discoloration extended to the sternum. A computed tomography scan showed pronounced swelling of the facial soft tissue and the right sinus cavity completely filled with blood. The patient was kept hospitalised for 3 days until regression of the swelling was attained and acceptable oral function was regained. Conclusion: Transcrestal SFE is often recommended to the less experienced surgeon before the lateral window technique due to fewer complications and lower morbidity. The present case illustrates that severe complications may accompany transcrestal SFE. Although rare, clinicians performing SFEshould be aware of this potential risk. Conflict-of-interest statement: The authors report to have no financial or personal relationships with people, companies or organisations that could inappropriately influence the present paper. [ABSTRACT FROM AUTHOR]

Published
2012

40. Membrane mobility and microdomain association of the dopamine transporter studied with fluorescence correlation spectroscopy and fluorescence recovery after photobleaching

Author

Samuvel, Devadoss J., Adkins, Erika M., Fog, Jacob U., Eriksen, Jacob, Jayanthi, Lankupalle D., Ramamoorthy, Sammanda, Gether, Ulrik, and Vaegter, Christian Bjerggaard

Subjects
Dopamine -- Analysis, Cell membranes -- Analysis, Cytoskeleton -- Analysis, Biological sciences, Chemistry
Abstract

The article investigates the association of the dopamine transporter (DAT) with lipid microdomains in the plasma membrane and the cytoskeleton. The findings propose that the association serves to regulate both the lateral mobility of the transporter and its transport capacity.

Published
2007

42. Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains

Author

Rahbek-Clemmensen, Troels, Lycas, Matthew D., Erlendsson, Simon, Eriksen, Jacob, Apuschkin, Mia, Vilhardt, Frederik, Jorgensen, Trine N., Hansen, Freja H., Gether, Ulrik, Rahbek-Clemmensen, Troels, Lycas, Matthew D., Erlendsson, Simon, Eriksen, Jacob, Apuschkin, Mia, Vilhardt, Frederik, Jorgensen, Trine N., Hansen, Freja H., and Gether, Ulrik

Abstract

Dopamine regulates reward, cognition, and locomotor functions. By mediating rapid reuptake of extracellular dopamine, the dopamine transporter is critical for spatiotemporal control of dopaminergic neurotransmission. Here, we use super-resolution imaging to show that the dopamine transporter is dynamically sequestrated into cholesterol-dependent nanodomains in the plasma membrane of presynaptic varicosities and neuronal projections of dopaminergic neurons. Stochastic optical reconstruction microscopy reveals irregular dopamine transporter nanodomains (∼70 nm mean diameter) that were highly sensitive to cholesterol depletion. Live photoactivated localization microscopy shows a similar dopamine transporter membrane organization in live heterologous cells. In neurons, dual-color dSTORM shows that tyrosine hydroxylase and vesicular monoamine transporter-2 are distinctively localized adjacent to, but not overlapping with, the dopamine transporter nanodomains. The molecular organization of the dopamine transporter in nanodomains is reversibly reduced by short-term activation of NMDA-type ionotropic glutamate receptors, implicating dopamine transporter nanodomain distribution as a potential mechanism to modulate dopaminergic neurotransmission in response to excitatory input.

Published
2017

43. A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

Author

Christiansen, Mia Apuschkin, Stilling, Sara, Rahbek-Clemmensen, Troels, Sørensen, Gunnar, Fortin, Guillaume, Herborg Hansen, Freja, Eriksen, Jacob, Trudeau, Louis-Eric, Egerod, Kristoffer, Gether, Ulrik, Rickhag, Karl Mattias, Christiansen, Mia Apuschkin, Stilling, Sara, Rahbek-Clemmensen, Troels, Sørensen, Gunnar, Fortin, Guillaume, Herborg Hansen, Freja, Eriksen, Jacob, Trudeau, Louis-Eric, Egerod, Kristoffer, Gether, Ulrik, and Rickhag, Karl Mattias

Abstract

Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting only 20 000-30 000 neurons in mice, and development of novel tools to identify these cells is warranted. Here, a bacterial artificial chromosome mouse line [Dat1-enhanced green fluorescent protein (eGFP)] from the Gene Expression Nervous System Atlas (GENSAT) that expresses eGFP under control of the dopamine transporter (DAT) promoter was characterized. Confocal microscopy analysis of brain sections showed strong eGFP signal reporter in midbrain regions and striatal terminals that co-localized with the DAergic markers DAT and tyrosine hydroxylase (TH). Thorough quantification of co-localization of the eGFP reporter signal with DAT and TH in the ventral midbrain showed that a vast majority of eGFP-expressing neurons are DAergic. Importantly, expression profiles also revealed DAergic heterogeneity when comparing substantia nigra and ventral tegmental area. Dat1-eGFP mice showed neither change in synaptosomal DA uptake nor altered levels of DAT and TH in both striatum and midbrain. No behavioural difference between Dat1-eGFP and wild-type was found, suggesting that the strain is not aberrant. Finally, cell populations highly enriched in DAergic neurons can be obtained from postnatal mice by fluorescence-activated cell sorting and the sorted neurons can be cultured in vitro. The current investigation demonstrates that eGFP expression in this mouse line is selective for DAergic neurons, suggesting that the Dat1-eGFP mouse strain constitutes a promising tool for delineating new aspects of DA biology.

Published
2015

44. Cellular regulation of the dopamine transporter

Author

Eriksen, Jacob

Subjects
nervous system, parasitic diseases, mental disorders
Abstract

Dopamintransporteren er ansvarlig for genoptag af dopamin fra den synaptiske kløft og er det primære mål for virkningen af udbredte psykostimulantia så som kokain og amfetamin. Selvom DAT spiller en central rolle for virkningen af psykostimulantia, så er viden om fordeling og 'trafficking' af DAT i endogene systemer begrænset. I nærværende studie har vi brugt fluorescensmærkede kokainanaloger med høj affinitet for DAT. Disse kokainanaloger muliggør visualisering af DAT i levende primærkulturer af dopaminerge kulturer. I de dopaminerge nerveceller var DAT ensartet fordelt i plasma membranen både i soma og i nervecellens udløbere. FRAP (fluoresecens recovery after photobleaching) eksperimenter viste bidirektionel bevægelse af DAT, og desuden var der evidens for meget mobil DAT i både udløbere og varikositeter. DAT udviste konstitutiv endocytose og blev ophobet i vesikulære strukturer, der muligvis repræsenterer en intracellulær pulje af DAT. Den konstitutive endocytose kunne blokeres af lentiviral medieret ekspression af dominant negativ dynamin 1, og konstitutiv internaliseret DAT co-lokaliserede til dels med både EGFP-Rab5 og transferrin receptoren. Overraskende var DAT internalisering ikke påvirket af protein kinase C (PKC) aktivitet i vores primærkulturer af dopaminerge nerveceller. Hverken stimulering af PKC med PMA eller ved at hæmme PKC med GF109203X påvirkede internaliseringen eller dopaminoptag. Disse resultater er forskellige fra observationer i cellelinier, som exogent udtrykker DAT og sætter spørgsmålstegn ved paradigmet om PKC-medieret regulering af DAT i dopaminerge nerveceller. For yderligere at karakterisere den konstitutive internalisering, som vi observerede i de dopaminerge neuroner anvendte vi flere forskellige strategier til at detektere DAT i både cellelinier og dopaminerge nerveceller. For at undersøge internalisering af eksogent udtrykt DAT brugte vi et konstrukt med DAT N-terminalen fusioneret med den intracellulære del af enkelt transmembran domæne proteinet Tac for herved at skabe en ekstracellulær antistof-epitop. Når dette Tac-DAT fusionsprotein blev udtrykt i HEK293 celler udviste det funktionelle egenskaber svarende til vildtype transporteren og blev internaliseret i lighed med denne. I et ELISA eksperiment kunne vi kvantificere en konstitutiv tidsafhænigig DAT internaliserng i HEK293 og den medfølgende intracellulære akkumulering blev øget af leupeptin, en hæmmer af lysosomal degradering. Dette indikerer at Tac-DAT delvist blev sorteret til lysosomal degradering. For at videre undersøge denne hypotese udtrykte vi TacDAT i den dopaminerge cellelinie 1Rb3An27, og her undersøgte vi sorteringen af TacDAT v.h.a. co-udtryk af endosomale markører koblet til EGFP. Kvantificering viste at internaliseret TacDAT kolokaliserede med Rab7, som lokaliserer til sen endosomale vesikler, et forstadie til lysosomer. TacDAT kolokaliserede signifikant mere med Rab7 end Rab11, som lokaliserer til en anden type 'recycling' endosomer. For at undersøge om dette også var gældende for konstitutivt internaliseret DAT enodgent, udtrykte vi EGFP-Rab markørerne v.h.a. lentivirus i primærkulturer med dopaminerge nerveceller. Ved hjælp af kokain-analogen, JHC 1-64 observerede vi at konstitutivt internaliseret DAT colokaliserede med Rab7 og ikke Rab11. Desuden var der en udpræget colokalisering mellem DAT og den lysosomale markør LysoTracker. Vi foreslår derfor at konstitutivt internaliseret DAT sorteres til degradering via rab7 positive vesikler til lysosomer både i cellelinier og primærkulturer med dopaminerge nerveceller, som udtrykker DAT endogent. Samlet giver resultaterne et billede af en dynamisk opretholdelse DAT homøostase i dopaminerge nerveceller. The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft and is a target for widely abused psychostimulants such as cocaine and amphetamine. Nonetheless, little is known about the cellular distribution and trafficking of natively expressed DAT. DAT and its trafficking was visualized in cultured live midbrain dopaminergic (DA) neurons using novel fluorescently tagged cocaine analogs. The ligands enabled specific labelling and visualization of DAT in live neurons. In the DA neurons, DAT was uniformly distributed in the plasma membrane of the soma, the neuronal extensions, and varicosities along these extensions. Moreover, DAT was constitutively internalized into vesicular structures and the internalization was blocked by lentiviralmediated expression of dominant-negative dynamin. DAT internalization and function was not affected by activation of protein kinase C (PKC) with phorbol-12-myristate-13-acetate (PMA) or by inhibition with staurosporine or GF109203X. These data are in contrast to findings for DAT in transfected heterologous cells and challenge the paradigm that trafficking and cellular distribution of endogenous DAT is subject to regulation by PKC. To further characterize the intracellular pool of constitutively endocytosed DAT several strategies were employed in both cell lines and cultured DA neurons. First, to investigate the constitutive trafficking of heterologously expressed DAT we fused the N-terminus of DAT to the intracellular tail of the single-membrane spanning protein Tac, thereby creating an extracellular antibody epitope. Upon expression in HEK293 cells this TacDAT fusion protein displayed functional properties similar to the wild type transporter. In an ELISA based internalization assay, TacDAT intracellular accumulation was increased by inhibitors of lysosomal degradation and moreover TacDAT colocalized with the late endosomal marker Rab7. In the DA cell line 1Rb3An27 TacDAT also co-localized with EGFP-Rab7 and not with the recycling endosomal marker EGFP-Rab11. To assess whether sorting to late endosomes/lysosomes was a property also inherent to natively expressed transporter, DAT was visualized directly in cultured DA neurons using the fluorescent cocaine analog JHC 1-64. These data showed pronounced colocalization upon constitutive internalization with Lysotracker, a late endosomal/lysosomal marker; however only little cololization was observed with Alexa488-conjugated transferrin. Additionally, when expressing EGFP-Rab7 with lentivirus in cultured DA neurons a marked co-localization between JHC 1-64 and EGFP-Rab7 was observed. The data suggest that constitutively internalized DAT primarily is targeted to late endosomes and lysosomes both in heterologous cells and in cultured DA neurons.DAT has been shown to be regulated by the dopamine D2 receptor (D2R), the primary target foranti-psychotics, through a direct interaction. D2R is among other places expressed as an autoreceptor in DA neurons. Transient over-expression of DAT with D2R in HEK293 cells reduced surface expression of D2R while DAT surface levels remained unaffected. Furthermore ß-Arrestin2 recruitment to D2R was compromised and D2R-mediated inhibition of cAMP accumulation was reduced as a consequence of the reduced surface level expression of D2R. The effects of DAT on D2R surface expression and signalling was not unique for DAT and D2R. Thus, transient coexpression of ß2AR with DAT resulted in reduced surface levels of ß2AR. In addition, coexpression of the serotonin transporter with D2R appeared to modulate the ß-Arrestin2 recruitment to D2R and the D2R-mediated inhibition of cAMP accumulation in a manner similar to coexpression of DAT. The data suggest that DAT affect D2R function and expression with no apparent specificity.

Published
2010

45. Membrane mobility and microdomain association of the dopaminetransporter studied with fluorescence correlation spectroscopy and fluorescence recovery after photobleaching:Microdomain association of the dopamine transporter

Author

Adkins, Erika, Samuvel, Devadoss, Fog, Jacob, Eriksen, Jacob, Jayanthi, Lankupalle, Vægter, Christian Bjerggaard, Ramamoorthy, Sammanda, and Gether, Ulrik

Subjects
nervous system
Abstract

To investigate microdomain association of the dopamine transporter (DAT), we employed FCS (fluorescence correlation spectroscopy) and FRAP (fluorescence recovery after photobleaching). In non-neuronal cells (HEK293), FCS measurements revealed for the YFP-DAT (DAT tagged with yellow fluorescent protein) a diffusion coefficient (D) of ~3.6 × 10-9 cm2/s, consistent with a relatively freely diffusible protein. In neuronally derived cells (N2a), we were unable to perform FCS measurements on plasma membrane-associated protein due to photobleaching, suggesting partial immobilization. This was supported by FRAP measurements that revealed a lower D and a mobile fraction of the YFP-DAT in N2a cells compared to HEK293 cells. Comparison with the EGFP-EGFR (epidermal growth factor receptor) and the EGFP-beta2AR (beta2 adrenergic receptor) demonstrated that this observation was DAT specific. Both the cytoskeleton-disrupting agent cytochalasin D and the cholesterol-depleting agent methyl-beta-cyclodextrin (mbCD) increased the lateral mobility of the YFP-DAT but not that of the EGFP-EGFR. The DAT associated in part with membrane raft markers both in the N2a cells and in rat striatal synaptosomes as assessed by sucrose density gradient centrifugation. Raft association was further confirmed in the N2a cells by cholera toxin B patching. It was, moreover, observed that cholesterol depletion, and thereby membrane raft disruption, decreased both the Vmax and KM values for [3H]dopamine uptake without altering DAT surface expression. In summary, we propose that association of the DAT with lipid microdomains in the plasma membrane and/or the cytoskeleton serves to regulate both the lateral mobility of the transporter and its transport capacity

Published
2007

46. A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter

Author

Rickhag, Karl Mattias, Hansen, Freja Herborg, Sørensen, Gunnar, Strandfelt, Kristine Nørgaard, Andresen, Bjørn, Gotfryd, Kamil, Madsen, Kenneth L, Vestergaard-Klewe, Ib, Ammendrup-Johnsen, Ina, Eriksen, Jacob, Newman, Amy H, Füchtbauer, Ernst-Martin, Gomeza, Jesus, Woldbye, David P D, Wörtwein, Gitta, Gether, Ulrik, Rickhag, Karl Mattias, Hansen, Freja Herborg, Sørensen, Gunnar, Strandfelt, Kristine Nørgaard, Andresen, Bjørn, Gotfryd, Kamil, Madsen, Kenneth L, Vestergaard-Klewe, Ib, Ammendrup-Johnsen, Ina, Eriksen, Jacob, Newman, Amy H, Füchtbauer, Ernst-Martin, Gomeza, Jesus, Woldbye, David P D, Wörtwein, Gitta, and Gether, Ulrik

Abstract

The dopamine transporter mediates reuptake of dopamine from the synaptic cleft. The cellular mechanisms controlling dopamine transporter levels in striatal nerve terminals remain poorly understood. The dopamine transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different dopamine transporter knock-in mice with disrupted PDZ-binding motifs (dopamine transporter-AAA and dopamine transporter+Ala) are characterized by dramatic loss of dopamine transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured dopaminergic neurons and striatal slices from dopamine transporter-AAA mice, we find markedly reduced dopamine transporter surface levels and evidence for enhanced constitutive internalization. In dopamine transporter-AAA neurons, but not in wild-type neurons, surface levels are rescued in part by expression of a dominant-negative dynamin mutation (K44A). Our findings suggest that PDZ-domain interactions are critical for synaptic distribution of dopamine transporter in vivo and thereby for proper maintenance of dopamine homoeostasis.

Published
2013

47. Protein interacting with C kinase 1 (PICK1) reduces reinsertion rates of interaction partners sorted to Rab11-dependent slow recycling pathway

Author

Madsen, Kenneth Lindegaard, Thorsen, Thor Seneca, Rahbek-Clemmensen, Troels, Eriksen, Jacob Møller, Gether, Ulrik, Madsen, Kenneth Lindegaard, Thorsen, Thor Seneca, Rahbek-Clemmensen, Troels, Eriksen, Jacob Møller, and Gether, Ulrik

Abstract

The scaffolding protein PICK1 (protein interacting with C kinase 1) contains an N-terminal PSD-95/Discs large/ZO-1 (PDZ) domain and a central lipid-binding Bin/amphiphysin/Rvs (BAR) domain. PICK1 is thought to regulate trafficking of its PDZ binding partners but different and even opposing functions have been suggested. Here, we apply ELISA-based assays and confocal microscopy in HEK293 cells with inducible PICK1 expression to assess in an isolated system the ability of PICK1 to regulate trafficking of natural and engineered PDZ binding partners. The dopamine transporter (DAT), which primarily sorts to degradation upon internalization, did not form perinuclear clusters with PICK1, and PICK1 did not affect DAT internalization/recycling. However, transfer of the PICK1-binding DAT C terminus to the β(2)-adrenergic receptor, which sorts to recycling upon internalization, led to formation of PICK1 co-clusters in Rab11-positive compartments. Furthermore, PICK1 inhibited Rab11-mediated recycling of the receptor in a BAR and PDZ domain-dependent manner. In contrast, transfer of the DAT C terminus to the δ-opioid receptor, which sorts to degradation, did not result in PICK1 co-clusters or any change in internalization/recycling. Further support for a role of PICK1 determined by its PDZ cargo was obtained for the PICK1 interaction partner prolactin-releasing peptide receptor (GPR10). GPR10 co-localized with Rab11 and clustered with PICK1 upon constitutive internalization but co-localized with the late endosomal marker Rab7 and did not cluster with PICK1 upon agonist-induced internalization. Our data suggest a selective role of PICK1 in clustering and reducing the recycling rates of PDZ domain binding partners sorted to the Rab11-dependent recycling pathway.

Published
2012

48. Severe bleeding after sinus floor elevation using the transcrestal technique:a case report

Author

Jensen, Simon Storgard, Eriksen, Jacob, Schiodt, Morten, Jensen, Simon Storgard, Eriksen, Jacob, and Schiodt, Morten

Abstract

AIM: To present a rare but clinically significant complication to sinus floor elevation (SFE) using the transcrestal technique.MATERIALS AND METHODS: Transcrestal SFE with simultaneous implant placement was performed in the maxillary right second premolar region of a healthy 70-year-old woman with no history of a bleeding disorder.RESULTS: The patient reported to the emergency care unit a few hours after the surgery with ongoing bleeding and progressive swelling of especially the right side of the midface. The buccal swelling did not allow the patient to close her mouth and the discoloration extended to the sternum. A computed tomography scan showed pronounced swelling of the facial soft tissue and the right sinus cavity completely filled with blood. The patient was kept hospitalised for 3 days until regression of the swelling was attained and acceptable oral function was regained.CONCLUSION: Transcrestal SFE is often recommended to the less experienced surgeon before the lateral window technique due to fewer complications and lower morbidity. The present case illustrates that severe complications may accompany transcrestal SFE. Although rare, clinicians performing SFE should be aware of this potential risk.

Published
2012

49. Eriksen, Jacob

Author

Eriksen, Jacob and Eriksen, Jacob

Published
2012

50. SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

Author

Kristensen, Anders S, Andersen, Jacob, Jørgensen, Trine N, Sørensen, Lena, Eriksen, Jacob, Løland, Claus Juul, Strømgaard, Kristian, Gether, Ulrik, Kristensen, Anders S, Andersen, Jacob, Jørgensen, Trine N, Sørensen, Lena, Eriksen, Jacob, Løland, Claus Juul, Strømgaard, Kristian, and Gether, Ulrik

Abstract

The neurotransmitter transporters (NTTs) belonging to the solute carrier 6 (SLC6) gene family (also referred to as the neurotransmitter-sodium-symporter family or Na(+)/Cl(-)-dependent transporters) comprise a group of nine sodium- and chloride-dependent plasma membrane transporters for the monoamine neurotransmitters serotonin (5-hydroxytryptamine), dopamine, and norepinephrine, and the amino acid neurotransmitters GABA and glycine. The SLC6 NTTs are widely expressed in the mammalian brain and play an essential role in regulating neurotransmitter signaling and homeostasis by mediating uptake of released neurotransmitters from the extracellular space into neurons and glial cells. The transporters are targets for a wide range of therapeutic drugs used in treatment of psychiatric diseases, including major depression, anxiety disorders, attention deficit hyperactivity disorder and epilepsy. Furthermore, psychostimulants such as cocaine and amphetamines have the SLC6 NTTs as primary targets. Beginning with the determination of a high-resolution structure of a prokaryotic homolog of the mammalian SLC6 transporters in 2005, the understanding of the molecular structure, function, and pharmacology of these proteins has advanced rapidly. Furthermore, intensive efforts have been directed toward understanding the molecular and cellular mechanisms involved in regulation of the activity of this important class of transporters, leading to new methodological developments and important insights. This review provides an update of these advances and their implications for the current understanding of the SLC6 NTTs.

Published
2011

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