10 results on '"Andrea Gerstner"'
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2. Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1
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Silke Haverkamp, Martin Biel, Stylianos Michalakis, Mathias W. Seeliger, Andrea Gerstner, Niyazi Acar, King Wai Yau, Heidi Geiger, Robert Mader, Sabine Hüttl, Dong Gen Luo, Kristiane Hudl, Alexander Pfeifer, Markus Moser, Ludwig Maximilians University of Munich, University Eye Hospital Tuebingen, Johns Hopkins University (JHU), Centre des Sciences du Goût et de l'Alimentation (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Department of Neuroanatomy, Universität Leipzig [Leipzig], Max Planck Institute of Biochemistry (MPIB), and Max-Planck-Gesellschaft
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Retinal degeneration ,genetic structures ,Apoptosis ,CONES (RETINA)PATHOLOGY ,EYE ,P.H.S ,Ion Channels ,RETINAL DEGENERATION GENETICS ,GENE DELETION ,RESEARCH SUPPORT ,chemistry.chemical_compound ,0302 clinical medicine ,Retinal Rod Photoreceptor Cells ,[SDV.IDA]Life Sciences [q-bio]/Food engineering ,CHANNELS BIOSYNTHESIS GENETICS PHYSIOLOGY ,Cyclic nucleotide-gated ion channel ,Mice, Knockout ,Genetics ,0303 health sciences ,medicine.diagnostic_test ,General Neuroscience ,Retinal Degeneration ,ROD OUTER ,Rod Cell Outer Segment ,Cell biology ,APOPTOSIS GENETICS ,NEUROLOGIA PATHOLOGY ,Retinal Cone Photoreceptor Cells ,EXONS ,Neuroglia ,Protein subunit ,PHOTOTRANSDUCTION PHYSILOGY ,Cyclic Nucleotide-Gated Cation Channels ,Biology ,PROTEINS BIOSYNTHESIS GENETICS ,SEGMENTS METABOLISM ,Article ,Retina ,N.I.H ,EXTRAMURAL ,03 medical and health sciences ,RODS(RETINA)PATHOLOGY ,Retinitis pigmentosa ,medicine ,[SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering ,ION ,Eye Proteins ,PHYSIOLOGY ,Vision, Ocular ,030304 developmental biology ,ANIMALS ,Retinal ,GENETIQUE ,INBRED C57BL ,medicine.disease ,Mice, Inbred C57BL ,MICE ,KNOCKOUT ,RETINA PATHOLOGY AND PHYSIOLOGY ,chemistry ,ELECTRORETINOGRAPHY ,sense organs ,030217 neurology & neurosurgery ,Electroretinography - Abstract
Cyclic nucleotide-gated (CNG) channels are important mediators in the transduction pathways of rod and cone photoreceptors. Native CNG channels are heterotetramers composed of homologous A and B subunits. In heterologous expression systems, B subunits alone cannot form functional CNG channels, but they confer a number of channel properties when coexpressed with A subunits. To investigate the importance of the CNGB subunitsin vivo, we deleted theCNGB1gene in mice. In the absence of CNGB1, only trace amounts of the CNGA1 subunit were found on the rod outer segment. As a consequence, the vast majority of isolated rod photoreceptors in mice lackingCNGB1(CNGB1-/-) failed to respond to light. In electroretinograms (ERGs),CNGB1-/-mice showed no rod-mediated responses. The rods also showed a slow-progressing degeneration caused by apoptotic death and concurred by retinal gliosis. Cones were primarily unaffected and showed normal ERG responses up to 6 months, but they started to degenerate in later stages. At the age of ∼1 year,CNGB1-/-animals were devoid of both rods and cones. Our results show that CNGB1 is a crucial determinant of native CNG channel targeting. As a result of the lack of rod CNG channels,CNGB1-/-mice develop a retinal degeneration that resembles human retinitis pigmentosa.
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- 2005
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3. Loss of CNGB1 protein leads to olfactory dysfunction and subciliary cyclic nucleotide-gated channel trapping
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Sabine Hüttl, Christian H. Wetzel, Jonathan Bradley, Marc Spehr, Xiangang Zong, Andrea Gerstner, Martin Biel, Johannes Reisert, King Wai Yau, Heidi Geiger, Alexander Pfeifer, Hanns Hatt, and Stylianos Michalakis
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Male ,medicine.medical_specialty ,Protein subunit ,Cyclic Nucleotide-Gated Cation Channels ,Olfaction ,Biology ,Biochemistry ,Ion Channels ,Article ,Mice ,Internal medicine ,medicine ,Animals ,Cyclic nucleotide-gated ion channel ,Molecular Biology ,Ion channel ,Mice, Knockout ,Olfactory receptor ,Nucleotides ,Body Weight ,Cell Biology ,Olfactory Bulb ,Olfactory bulb ,Cell biology ,Electrophysiology ,Endocrinology ,medicine.anatomical_structure ,Calcium-Calmodulin-Dependent Protein Kinases ,Female ,Olfactory epithelium - Abstract
Olfactory receptor neurons (ORNs) employ a cyclic nucleotide-gated (CNG) channel to generate a receptor current in response to an odorant-induced rise in cAMP. This channel contains three types of subunits, the principal CNGA2 subunit and two modulatory subunits (CNGA4 and CNGB1b). Here, we have analyzed the functional relevance of CNGB1 for olfaction by gene targeting in mice. Electro-olfactogram responses of CNGB1-deficient (CNGB1-/-) mice displayed a reduced maximal amplitude and decelerated onset and recovery kinetics compared with wild-type mice. In a behavioral test, CNGB1-/- mice exhibited a profoundly decreased olfactory performance. Electrophysiological recordings revealed that ORNs of CNGB1-/- mice weakly expressed a CNG current with decreased cAMP sensitivity, very rapid flicker-gating behavior and no fast modulation by Ca2+-calmodulin. Co-immunoprecipitation confirmed the presence of a CNGA2/CNGA4 channel in the olfactory epithelium of CNGB1-/- mice. This CNGA2/CNGA4 channel was targeted to the plasma membrane of olfactory knobs, but failed to be trafficked into olfactory cilia. Interestingly, we observed a similar trafficking defect in mice deficient for the CNGA4 subunit. In conclusion, these results demonstrate that CNGB1 has a dual function in vivo. First, it endows the olfactory CNG channel with a variety of biophysical properties tailored to the specific requirements of olfactory transduction. Second, together with the CNGA4 subunit, CNGB1 is needed for ciliary targeting of the olfactory CNG channel.
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- 2006
4. A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase
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Christian Wahl-Schott, Andrea Gerstner, Ludwig Baumann, Zhengjun Chen, Haixin Yuan, Heike Abicht, Barbara Much, Xiangang Zong, Martin Biel, Rongxia Li, Christian Eckert, Longfou Fang, Pavel Mistrik, Stylianos Michalakis, and Rong Zeng
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Potassium Channels ,Phenylalanine ,Cyclic Nucleotide-Gated Cation Channels ,Muscle Proteins ,SH2 domain ,Kidney ,Biochemistry ,SH3 domain ,Ion Channels ,Mass Spectrometry ,Cell Line ,Membrane Potentials ,src Homology Domains ,chemistry.chemical_compound ,Mice ,Two-Hybrid System Techniques ,Yeasts ,HCN channel ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,Animals ,Humans ,Amino Acid Sequence ,Phosphorylation ,Molecular Biology ,Conserved Sequence ,biology ,Chemistry ,Tyrosine phosphorylation ,Cell Biology ,Membrane hyperpolarization ,Cell biology ,Electrophysiology ,Kinetics ,src-Family Kinases ,Cyclic nucleotide-binding domain ,biology.protein ,Mutagenesis, Site-Directed ,Tyrosine ,Tyrosine kinase ,Ion Channel Gating ,Proto-oncogene tyrosine-protein kinase Src ,Plasmids - Abstract
Hyperpolarization-activated cyclic nucleotide-gated channels (HCN1-4) play a crucial role in the regulation of cell excitability. Importantly, they contribute to spontaneous rhythmic activity in brain and heart. HCN channels are principally activated by membrane hyperpolarization and binding of cAMP. Here, we identify tyrosine phosphorylation by Src kinase as another mechanism affecting channel gating. Inhibition of Src by specific blockers slowed down activation kinetics of native and heterologously expressed HCN channels. The same effect on HCN channel activation was observed in cells cotransfected with a dominant-negative Src mutant. Immunoprecipitation demonstrated that Src binds to and phosphorylates native and heterologously expressed HCN2. Src interacts via its SH3 domain with a sequence of HCN2 encompassing part of the C-linker and the cyclic nucleotide binding domain. We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity.
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- 2005
5. Cyclic Nucleotide-Regulated Cation Channels
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Martin Biel and Andrea Gerstner
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Membrane potential ,Stretch-activated ion channel ,Cyclic nucleotide ,chemistry.chemical_compound ,Voltage-gated ion channel ,Biochemistry ,Chemistry ,T-type calcium channel ,Biophysics ,Depolarization ,Cardiac action potential ,Cyclic nucleotide-gated ion channel - Abstract
Cyclic nucleitides exert their physiological effects by binding to four major classes of cellular receptors: cAMP- and cGMP-dependent protein kinases, cyclic GMP-regulated phosphodiesterases, cAMP-binding guanine nucleotide exchange factors, and cyclic nucleotide-regulated cation channels. Cyclic nucleotide-regulated cation channels are unique among these receptors because their activation is directly coupled to the influx of extracellular cations into the cytoplasm and to the depolarization of the plasma membrane. Two families of channels regulated by cyclic nucleotides have been identified, the cyclic nucleotide-gated (CNG) channels and the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. The two channel classes differ from each other with regard to their mode of activation. CNG channels are opened by direct binding of cAMP or cGMP. In contrast, HCN channels are principally operated by voltage. These channels open at hyperpolarized membrane potentials and close on depolarization. Apart from their voltage senstivity, HCN channels are also activated directly by cyclic nucleotides, which act by increasing the channel open probability.
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- 2003
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6. Contributors
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John M. Abrams, John P. Adelman, Joseph L. Alcorn, Dario R. Alessi, Emil Alexov, Simon Alford, Kari Alitalo, James P. Allison, Steven C. Almo, Christelle Alory, Aymen Al-Shamkhani, Sally A. Amundson, Carl W. Anderson, Jannik N. Andersen, Peter Angel, Ettore Appella, William J. Arendshorst, Steve Arkinstall, Anjon Audhya, Joseph Avruch, Gary D. Bader, Cinzia Bagala, William E. Balch, Jesus Balsinde, Utpal Banerjee, David Barford, Dafna Bar-Sagi, Perry F. Bartlett, Philippe I.H. Bastiaens, Chiara Battelli, Linnea M. Baudhuin, Andrew J. Beavil, Rebecca L. Beavil, Joseph A. Beavo, Elsa Bello-Reuss, Stephen Bellum, Juan Carlos Izpisúa Belmonte, Craig B. Bennett, Jeffrey L. Benovic, Michael J. Berridge, Penny J. Beuning, Rashna Bhandari, Ananya Bhattacharya, Martin Biel, Vincent A. Bielinski, Hana Bilak, Lutz Birnbaumer, Geoff Birrell, Gail A. Bishop, Trillium Blackmer, Perry J. Blackshear, Christine Blattner, Mordecai P. Blaustein, Gary M. Bokoch, Lynda F. Bonewald, Marco Bonomi, Michelle A. Booden, Charles Boone, Martin D. Bootman, Johannes L. Bos, Jane M. Bradbury, Ralph A. Bradshaw, Anne R. Bresnick, Lena Brevnova, Ross I. Brinkworth, Michael S. Brown, Steven A. Brown, Anne Brunet, Robert Bucki, Robert D. Burgoyne, Janice E. Buss, Ronald A. Butow, Javier Capdevila, Ernesto Carafoli, Cathrine R. Carlson, Graham Carpenter, Juan J. Carrillo, Patrick J. Casey, William A. Catterall, Richard A. Cerione, Gianni Cesareni, Andrew C. Chan, Geoffrey Chang, Moses V. Chao, Harry Charbonneau, Philip Chen, Alan Cheng, Chris Chiu, Dar-chone Chow, Ted D. Chrisman, Anne Elisabeth Christensen, Jee Y. Chung, Grant C. Churchill, Aaron Ciechanover, Gino Cingolani, Sylvie Claeysen, Jean Closset, Shamshad Cockcroft, Patricia T.W. Cohen, Philip Cohen, Roger J. Colbran, Clay E.S. Comstock, Marco Conti, Jackie D. Corbin, Daniela Corda, Sabine Costagliola, Rick H. Cote, Shaun R. Coughlin, L. Ashley Cowart, Adrienne D. Cox, Mark S. Cragg, José L. Crespo, Claudia Crosio, Christopher Daly, Sami Damak, Mary Dasso, Michael David, Anthony J. Davis, Roger J. Davis, Richard N. Day, Eva Degerman, Warren L. DeLano, Mark L. Dell'Acqua, Emmanuèle Délot, Bruce Demple, Edward A. Dennis, John M. Denu, Anna A. DePaoli-Roach, Channing J. Der, Johan de Rooij, Frederic de Sauvage, Peter N. Devreotes, Valérie Dewaste, Robert B. Dickson, Becky A. Diebold, Pier Paolo Di Fiori, Maria Di Girolamo, Julie Diplexcito, Jack E. Dixon, Robert W. Doms, Daniel J. Donoghue, Russell F. Doolittle, Stein Ove Døskeland, Wolfgang R.G. Dostmann, Matthias K. Dreyer, Guo Guang Du, Keyong Du, Michael R. Duchen, William G. Dunphy, Joanne Durgan, Michael L. Dustin, Peter A. Edwards, Jackson G. Egen, Lee E. Eiden, Elaine A. Elion, Scott Emr, Othmar G. Engelhardt, Christophe Erneux, Peter J. Espenshade, Edward D. Esplin, B. Mark Evers, Joanne L. Eyles, Sheelagh Fame, Marilyn Farquhar, Robert Feil, Gui-Jie Feng, Stanley Fields, James J. Fiordalisi, Richard A. Firtel, Garret A. Fitzgerald, Andrew Flint, Marco Foiani, Barry Marc Forman, Albert J. Fornace, Sharron H. Francis, Günter Fritz, David A. Fruman, Antony Galione, Chris S. Gandhi, David L. Garbers, K. Christopher Garcia, Benjamin Geiger, Larry Gerace, Andrea Gerstner, Amato J. Giaccia, Michele Giannattasio, Vincent Giguère, Christopher K. Glass, Martin J. Glennie, Jennifer L. Glick, Joseph L. Goldstein, Venkatesh Gopal, Myriam Gorospe, Cedric Govaerts, Paul R. Graves, Patrick W. Gray, Irene Graziani, Douglas R. Green, Michael E. Greenberg, Iva Greenwald, Haihua Gu, Nuri Gueven, J. Silvio Gutkind, Jesper Z. Haeggström, Alan Hall, Michael N. Hall, Otto Haller, Heidi E. Hamm, Yusef A. Hannun, Carl A. Hansen, T. Kendall Harden, D. Grahame Hardie, Kiminori Hasegawa, Phillip T. Hawkins, Timothy A.J. Haystead, Xiao-lin He, Claus W. Heizmann, Carl-Henrik Heldin, Michelle L. Hermiston, Peter Herrlich, Elizabeth A. Hewat, Bertil Hille, Douglas J. Hilton, K.A. Hinchliffe, Steffan N. Ho, Su-Chin Ho, Mark Hochstrasser, Franz Hofmann, Christopher W. Hogue, Wim G.J. Hol, Jocelyn Holash, Robert A. Holmgren, Barry Honig, Bruce S. Hostager, Stevan R. Hubbard, Michael Huber, Tony Hunter, Anna Huttenlocher, Sarah G. Hymowitz, James N. Ihle, Jean-Luc Imler, R.F. Irvine, Ehud Y. Isacoff, Xavier Iturrioz, Lars F. Iversen, Ravi Iyengar, Stephen P. Jackson, Lily Yeh Jan, Fabiola Janiak-Spens, Paul A. Janmey, Peter Gildsig Jansen, Sophie Jarriault, Jonathan A. Javitch, Elwood V. Jensen, Kristen Jepsen, E. Yvonne Jones, Katherine A. Jones, J. Dedrick Jordan, Jomon Joseph, Louis B. Justement, Yariv Kafri, Richard A. Kahn, Shin W. Kang, Arthur Karlin, Heidi R. Kast-Woelbern, Randal J. Kaufman, Andrius Kazlauskas, James H. Keen, Rolf Kemler, Bruce E. Kemp, Mary B. Kennedy, Matthew A. Kennedy, Ushio Kikkawa, Albert H. Kim, Soo-A Kim, Sung-Hou Kim, Youngjoo Kim, Kirst King-Jones, Chris Kintner, Saul Kivimäe, Claude B. Klee, Rüdiger Klein, Thomas Kleppisch, Steven A. Kliewer, Richard A. Klinghoffer, Juergen A. Knoblich, Bostjan Kobe, George Kochs, Monica Kong-Beltran, Rolf König, Albert C. Koong, Murray Korc, Daniel Kornitzer, Anthony A. Kossiakoff, Jun Kotera, M.V. Kovalenko, Tohru Kozasa, Sergei Kozlov, Keith G. Kozminski, Sonja Krugmann, John Kuriyan, Riki Kurokawa, Peter D. Kwong, Wi S. Lai, Elise Lamar, Millard H. Lambert, David G. Lambright, Doron Lancet, Reiko Landry, Wallace Y. Langdon, Lorene K. Langeberg, Paul Lasko, Vaughn Latham, Martin F. Lavin, Kevin A. Lease, Hakon Leffler, Mark A. Lemmon, Ann E. Leonard, Alexander Levitzki, Hong-Jun Liao, Lucy Liaw, Giordano Liberi, Heiko Lickert, Robert C. Liddington, Thomas M. Lincoln, Jürgen U. Linder, Maurine E. Linder, Hui Liu, Zhengchang Liu, Marja K. Lohela, Sarah H. Louie, Deirdre K. Luttrell, Louis M. Luttrell, Karen M. Lyons, S. Lance Macaulay, Michael Maceyka, Thomas Maciag, Fernando Macian, Carol MacKintosh, David H. MacLennan, Nadir A. Mahmood, Craig C. Malbon, Sohail Malik, Orna Man, Carol L. Manahan, Anna Mandinova, Vincent C. Manganiello, James L. Manley, Matthias Mann, Gerald Manning, Ed Manser, Marta Margeta-Mitrovic, Robert F. Margolskee, Julia Marinissen, Roy A. Mariuzza, Mina D. Marmor, G. Steven Martin, Karen H. Martin, Sergio E. Martinez, Michael B. Mathews, Bruce J. Mayer, Mark L. Mayer, Maria R. Mazzoni, Frank McCormick, Clare H. McGowan, Melissa M. McKay, Wallace L. McKeehan, Alison J. McLean, Anthony R. Means, Ruedi Meili, Jingwei Meng, Mark Merchant, Frank Mercurio, Graeme Milligan, Guo-Li Ming, Daniel L. Minor, Nadeem Moghal, Neils Peter H. Møller, Marco Mongillo, Marc Montminy, Randall T. Moon, Richard I. Morimoto, Stephen E. Moss, Helen R. Mott, Carla Mouta, Marco Muda, Marc C. Mumby, Gretchen A. Murphy, Marco Muzi-Falconi, Raghavendra Nagaraj, Stefan R. Nahorski, Angus C. Nairn, Piers Nash, Benjamin G. Neel, Alexandra C. Newton, Yasutomi Nishizuka, Joseph P. Noel, Ellen A.A. Nollen, Irene M.A. Nooren, Rodney O'Connor, Stefan Offermanns, Tsviya Olender, Shao-En Ong, Darerca Owen, Lisa J. Pagliari, Lily Pao, John Papaconstantinou, Leonardo Pardo, Hay-Oak Park, Young Chul Park, Peter J. Parker, J. Thomas Parsons, J.M. Passner, Tony Pawson, Achille Pelliccioli, J. Regino Perez-Polo, Norbert Perrimon, Fabrice G. Petite, Emmanuel Petroulakis, Samuel L. Pfaff, Jacob Piehler, Linda J. Pike, Michael J. Pinkoski, Fiona J. Pixley, Paolo Plevani, Mu-ming Poo, Tullioi Pozzan, Stephen M. Prescott, Igor Prudovsky, James W. Putney, Thomas Radimerski, Elzbieta Radzio-Andzelm, Prahlad T. Ram, Lucia Rameh, Danica Ramljak, Barbara Ranscht, Anjana Rao, Carol J. Raport, Jacqueline D. Reeves, Holger Rehman, Trevor W. Reichman, Eric Reiter, Michael A. Resnick, Michael Reth, Sue Goo Rhee, Joel D. Richter, Rodney L. Rietze, James M. Rini, Jürgen A. Ripperger, Josep Rizo, Janet D. Robishaw, H. Llewelyn Roderick, Robert G. Roeder, Larry R. Rohrschneider, David Ron, Michael G. Rosenfeld, Hans Rosenfeldt, Kent L. Rossman, Christopher B. Roth, Markus G. Rudolph, Anja Ruppelt, Lino Saez, Thomas P. Sakmar, Guy S. Salvesen, Paolo Sassone-Corsi, Charles L. Saxe, Beat W. Schäfer, Ueli Schibler, Christian W. Schindler, Tobias Schmelzle, Sandra L. Schmid, Anja Schmidt, Eric F. Schmidt, Gideon Schreiber, Joachim E. Schultz, Beat Schwaller, Klaus Schwamborn, Thue Schwartz, William F. Schwindinger, Giorgio Scita, John D. Scott, Shaun Scott, Thomas Seebeck, Charles N. Serhan, John B. Shabb, Andrey S. Shaw, Stephen B. Shears, Shirish Shenolikar, Lei Shi, Chanseok Shin, Kazuhiro Shiozaki, Kevan M. Shokat, Trevor J. Shuttleworth, David P. Siderovski, Steven A. Siegelbaum, Adam M. Silverstein, Robert H. Singer, Michael K. Skinner, Jill K. Slack-Davis, Stephen J. Smerdon, Graeme C.M. Smith, Guillaume Smits, Sarah M. Smolik, Jessica E. Smotrys, Emer M. Smyth, Jason T. Snyder, Naoko Sogame, Raffaella Soldi, John Sondek, Nahum Sonenberg, Erica Dutil Sonneberg, Lindsay G. Sparrow, Sarah Spiegel, Stephen R. Sprang, Deepak Srivastava, Robyn L. Stanfield, E. Richard Stanley, Deborah J. Stauber, Christopher Stefan, Lena Stenson-Holst, Len Stephens, Paul W. Sternberg, Paul C. Sternweis, Ruth Steward, John T. Stickney, Andrew W. Stoker, Stephen M. Strittmatter, Beth E. Stronach, Roland K. Strong, Robert M. Stroud, Thomas C. Südhof, Roger K. Sunahara, Brian J. Sutton, Sipeki Szabolcs, Xiao-Bo Tang, Kjetil Taskén, Hisashi Tatebe, Servane Tauszig-Delamasure, Colin W. Taylor, Garry L. Taylor, Laura J. Taylor, Susan S. Taylor, George Thomas, Robert P. Thomas, E. Brad Thompson, Michael J. Thompson, Janet M. Thornton, Carl S. Thummel, Hideaki Togashi, Amy Hin Yan Tong, Nicholas K. Tonks, Peter Tontonoz, M.K. Topham, Knut Martin Torgersen, Hien Tran, Michel L. Tremblay, Ming-Jer Tsai, Sophia Y. Tsai, Susan Tsunoda, Stewart Turley, Darren Tyson, Robert L. Van Etten, Gilbert Vassart, Peter J. Verveer, Virginie Vlaeminck, Abraham M. de Vos, Ty C. Voss, Robert Walczak, Graham C. Walker, John C. Walker, Gernot Walter, Mark R. Walter, Fen Wang, Jean Y.J. Wang, Weiru Wang, Richard J. Ward, Philip Wedegaertner, Christian Wehrle, Arthur Weiss, Jamie L. Weiss, Alan Wells, Claudia Werner, Ann H. West, Marie C. Weston, John K. Westwick, Anders Wetterholm, Morris F. White, Malcolm Whitman, Matt R. Whorton, Christian Wiesmann, Roger L. Williams, William D. Willis, Timothy M. Willson, Ian A. Wilson, Ofer Wiser, Matthew J. Wishart, Alfred Wittinghofer, James R. Woodgett, David K. Worthylake, Jeffrey L. Wrana, Hao Wu, Yijin Xiao, H. Eric Xu, Yan Xu, Zheng Xu, Michael B. Yaffe, Kenneth M. Yamada, Seun-Ah Yang, Wannian Yang, Yosef Yarden, Hong Ye, Weilan Ye, Todd O. Yeates, Helen L. Yin, John D. York, Edgar C. Young, Kenneth W. Young, Matthew A. Young, Michael W. Young, Minmin Yu, Nathan R. Zaccai, Manuela Zaccolo, Eli Zamir, Mark von Zastrow, Chao Zhang, Xuewu Zhang, Zhong-Yin Zhang, Wenhong Zhou, and Roya Zoraghi
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- 2003
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7. Molecular Cloning and Functional Characterization of a New Modulatory Cyclic Nucleotide-Gated Channel Subunit from Mouse Retina
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Xiangang Zong, Martin Biel, Franz Hofmann, and Andrea Gerstner
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genetic structures ,Macromolecular Substances ,Protein subunit ,Molecular Sequence Data ,Cyclic Nucleotide-Gated Cation Channels ,Molecular cloning ,Transfection ,Ion Channels ,Retina ,Cell Line ,Membrane Potentials ,Diltiazem ,Mice ,Animals ,Humans ,Amino Acid Sequence ,Cyclic nucleotide-gated ion channel ,ARTICLE ,Cloning, Molecular ,Peptide sequence ,Cyclic GMP ,Ion channel ,G alpha subunit ,biology ,Sequence Homology, Amino Acid ,General Neuroscience ,Molecular biology ,Recombinant Proteins ,Cell biology ,Rats ,biology.protein ,Calcium ,sense organs ,Sequence Alignment ,ATP synthase alpha/beta subunits ,Visual phototransduction - Abstract
Cyclic nucleotide-gated (CNG) channels play a key role in olfactory and visual transduction. Native CNG channels are heteromeric complexes consisting of the principal α subunits (CNG1–3), which can form functional channels by themselves, and the modulatory β subunits (CNG4–5). The individual α and β subunits that combine to form the CNG channels in rod photoreceptors (CNG1 + CNG4) and olfactory neurons (CNG2 + CNG4 + CNG5) have been characterized. In contrast, only an α subunit (CNG3) has been identified so far in cone photoreceptors. Here we report the molecular cloning of a new CNG channel subunit (CNG6) from mouse retina. The cDNA of CNG6 encodes a peptide of 694 amino acids with a predicted molecular weight of 80 kDa. Among the CNG channel subunits, CNG6 has the highest overall similarity to the CNG4 β subunit (47% sequence identity). CNG6 transcripts are present in a small subset of retinal photoreceptor cells and also in testis. Heterologous expression of CNG6 in human embryonic kidney 293 cells did not lead to detectable currents. However, when coexpressed with the cone photoreceptor α subunit, CNG6 induced a flickering channel gating, weakened the outward rectification in the presence of extracellular Ca2+, increased the sensitivity forl-cisdiltiazem, and enhanced the cAMP efficacy of the channel. Taken together, the data indicate that CNG6 represents a new CNG channel β subunit that may associate with the CNG3 α subunit to form the native cone channel.
- Published
- 2000
8. Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3
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Andrea Gerstner, Sascha Fauser, Gesine B. Jaissle, Konrad Kohler, Martin Biel, Andreas Ludwig, Alexander Pfeifer, Mathias W. Seeliger, Eberhart Zrenner, and Franz Hofmann
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Achromatopsia ,genetic structures ,Molecular Sequence Data ,Cyclic Nucleotide-Gated Cation Channels ,Biology ,Retinal Cone Photoreceptor Cells ,Ion Channels ,chemistry.chemical_compound ,Mice ,medicine ,Animals ,Eye Proteins ,Ion channel ,Regulation of gene expression ,Genetics ,GNAT2 ,Multidisciplinary ,Retinal ,Biological Sciences ,medicine.disease ,Cone (formal languages) ,Electrophysiology ,chemistry ,Gene Expression Regulation ,Biophysics ,sense organs ,Gene Deletion - Abstract
Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function.
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- 1999
9. Impaired Opsin Targeting and Cone Photoreceptor Migration in the Retina of Mice Lacking the Cyclic Nucleotide-Gated Channel CNGA3
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Stylianos Michalakis, Martin Biel, Silke Haverkamp, Franz Hofmann, Andrea Gerstner, and Heidi Geiger
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Opsin ,genetic structures ,Protein subunit ,Blotting, Western ,Cyclic Nucleotide-Gated Cation Channels ,Down-Regulation ,Outer plexiform layer ,Apoptosis ,Biology ,Ion Channels ,Mice ,Cyclic nucleotide ,chemistry.chemical_compound ,Cell Movement ,In Situ Nick-End Labeling ,medicine ,Animals ,Gliosis ,Eye Proteins ,Vision, Ocular ,Mice, Knockout ,Retina ,Reverse Transcriptase Polymerase Chain Reaction ,Retinal Degeneration ,Rod Opsins ,Biological Transport ,Anatomy ,Immunohistochemistry ,Cell biology ,medicine.anatomical_structure ,chemistry ,Synapses ,Knockout mouse ,Retinal Cone Photoreceptor Cells ,sense organs ,Gene Deletion ,Visual phototransduction - Abstract
PURPOSE: To characterize molecular and cellular changes in the mouse retina caused by the genetic deletion of the cone cyclic nucleotide-gated channel (CNG) subunit CNGA3. METHODS: Retinas of wild-type and CNGA3-deficient (CNGA3(-/-)) mice from 9 days up to 22 months of age were analyzed by immunohistochemistry, electron microscopy, and molecular biological methods. RESULTS: CNGA3(-/-) cones failed to transport opsins into outer segments, downregulated various proteins of the phototransduction cascade, and induced apoptotic death. Loss of CNGA3 did not affect the transcription of cone-specific genes. Cone degeneration was evident from the second postnatal week on, and it proceeded significantly faster in the ventral than in the dorsal part of the retina. Ventral cones were completely missing after the third postnatal month, whereas residual dorsal cones were present, even in 22-month-old knockout mice. CNGA3(-/-) cone somata exhibited profoundly delayed migration during postnatal development. At the time of eye opening, most CNGA3(-/-) cones had displaced somata localized close to or in the outer plexiform layer. These cones lacked the characteristic synaptic pedicle, but revealed synapselike contacts to second-order neurons at their somata. At later stages, most of the surviving CNGA3(-/-) cones had correctly located somata and morphologically normal synapses. CONCLUSIONS: The loss of CNGA3 impairs the targeting of cone opsins and the expression of other visual cascade proteins. In addition, CNGA3 appears to be essential for normal postnatal migration of cone somata. After loss of cone outer segment proteins, CNGA3(-/-) cones induce apoptotic cell death.
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- 2005
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10. Functional Characterization of the L-type Ca2+Channel Cav1.4α1 from Mouse Retina
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Ludwig Baumann, Andrea Gerstner, Xiangang Zong, Christian Wahl-Schott, and Martin Biel
- Subjects
Patch-Clamp Techniques ,Calcium Channels, L-Type ,Protein subunit ,Gene Expression ,Biology ,Kidney ,Transfection ,Retina ,Mice ,medicine ,Animals ,Humans ,Patch clamp ,Cloning, Molecular ,Isradipine ,Voltage-dependent calcium channel ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Membrane ,Dihydropyridine ,Antagonist ,Glutamate receptor ,Kidney metabolism ,Anatomy ,Calcium Channel Blockers ,Electrophysiology ,Mice, Inbred C57BL ,Calcium Channel Agonists ,Barium ,Biophysics ,Calcium ,medicine.drug - Abstract
Purpose To study the electrophysiological and pharmacological properties of the L-type Ca(2+) channel (LTCC) Ca(v)1.4alpha1 (alpha1F) subunit from mouse retina and assess their contributions to the native retinal channel. Methods The full-length cDNA of Ca(v)1.4alpha1 was cloned from murine retina in an RT-PCR approach. Ca(v)1.4alpha1 was expressed alone or together with the auxiliary alpha2delta1 and beta2a or beta3 subunits in HEK293 cells. The electrophysiological and pharmacological characteristics of L-type Ca(2+) and Ba(2+) inward currents (I(Ca) and I(Ba)) induced by Ca(v)1.4alpha1 were determined by the whole-cell configuration of the patch-clamp method and compared with currents induced by the cardiac and smooth muscle-type Ca(v)1.2alpha1 (alpha1C) channel. Results Ca(v)1.4alpha1-mediated I(Ba) was observed only when the alpha2delta1 and beta subunits were coexpressed. Current densities were approximately two times higher with beta2a than with beta3. I(Ba) activated faster and revealed much slower time-dependent inactivation than I(Ba) induced by Ca(v)1.2alpha1. Unlike in Ca(v)1.2alpha1, inactivation was not accelerated with Ca(2+) as the charge carrier, indicating the absence of Ca(2+)-dependent inactivation in Ca(v)1.4alpha1. Ca(v)1.4alpha1 exhibited voltage-dependent inactivation. The dihydropyridine (DHP) antagonist isradipine blocked Ca(v)1.4alpha1 with approximately 20-fold lower sensitivity than Ca(v)1.2alpha1. The agonistic DHP BayK 8644 stimulated maximum I(Ba) approximately sixfold. Ca(v)1.4alpha1 revealed only moderate sensitivities to L- and D-cis-diltiazem, with IC(50) in the micromolar range. Both enantiomers unexpectedly blocked Ca(v)1.4alpha1 with almost equal IC(50). Conclusions The data indicate that Ca(v)1.4alpha1 subunit constitutes the major molecular correlate of retinal L-type Ca(2+) current. Its intrinsic biophysical properties, in particular its unique inactivation properties, enable Ca(v)1.4alpha1 to provide a sustained I(Ca) over a voltage range such as required for tonic glutamate release at the photoreceptor synapse.
- Published
- 2004
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