August 9-12, 2004 – Copenhagen, Denmark
Organizing committee: Ulrik Gether, Orla Miller Larsson, Peter Høngaard Andersen, Arne Schousboe, Povl Krogsgaard-Larsen and Sven Frøkjær
Invited speakers and chairmen: Susan AMARA, U.S.A. – Peter Høngaard ANDERSEN, Denmark – Carmen ARAGÓN, Spain – Heinrich BETZ, Germany – Randy BLAKELY, U.S.A. – Klaus BØGESØ, Denmark – Marc G. CARON, U.S.A. – Niels Chr. DANBOLT, Norway – Robert EDWARDS, U.S.A. – Sven FRØKJÆR – Ulrik GETHER, Denmark – Bruno GIROS, France – Jonathan A. JAVITCH, U.S.A. – Baruch I. KANNER, Israel – Povl KROGSGAARD-LARSEN, Denmark – Orla Miller LARSSON, Denmark – Bertha MADRAS, U.S.A. – Peter MALONEY, U.S.A. – Isabelle M. MINTZ, U.S.A. – Michael W. QUICK, U.S.A. – Michael B. ROBINSON, U.S.A. – Jeffrey D. ROTHSTEIN, U.S.A. – Gary RUDNICK, U.S.A. – Arne SCHOUSBOE, Denmark – Shimon SCHULDINER, Israel – Harald SITTE, Austria – Davide TROTTI, U.S.A. – Robert J. VANDENBERG, Australia – H. Steve WHITE, U.S.A.
Synopsis: Transmembrane transport processes are fundamental for all living organisms. This is in particular reflected by the fact that close to 300 transport proteins are encoded by the human genome. Many of these are expressed in the brain and known to play a pathophysiological role in the development of mental disorders as well as neurological and neurodegenerative diseases. Three major classes of transporters dedicated to transmembrane translocation of neurotransmitters have been defined in the nervous system. These include the family of intracellular vesicular transporters, the class of Na+/Cl–coupled neurotransmitter transporters and the Na+-coupled glutamate transporters.
The vesicular transporters are responsible for concentrating neurotransmitters, such as dopamine, serotonin, norepinephrine, GABA (γ-aminobutyric acid), acetylcholine and glutamate, in the synaptic vesicles. On the other hand Na+/Cl–coupled neurotransmitter transporters and glutamate transporters play a pivotal role in controlling the concentration of these neurotransmitters in the extracellular space after their release into the synaptic cleft. In light of the critical physiological function of neurotransmitter transporters it is not surprising that several of these are important drug targets. Examples include the transporters for serotonin, dopamine and norepinephrine that are targets for the action of antidepressants and widely abused psychoactive compounds, such as cocaine, amphetamine and ‘ecstasy’, and transporters for GABA as targets for antiepileptic drugs. However, still many transport proteins in the brain represent unexplored targets for the action of putative new drugs. In this context it may be of particular interest that malfunction of glutamate transporters is associated with severe neurodegenerative disorders. Moreover, it is becoming increasingly clear that the transport systems are highly relevant for neuronal signaling of neurotransmitter homoestasis.
Benzon Symposium No. 51 is devoted to the neurotransmitter transporter topic.
The field is rapidly developing and during recent years significant progress has been made in our understanding of neurotransmitter transporter function both at the molecular level and in the living organism. The sessions will cover a broad spectrum of subjects with specific emphasis on transporter structure and dynamics, functional genomics in vitro and in vivo, as well as the role of neurotransmitter transporters in disease development and as drug targets.
Scientific Programme:
Arne SCHOUSBOE: Introduction
Marc CARON: Monoamine transporters: beyond reuptake
Session I: STRUCTURE, HETEROMERIC ASSEMBLY AND CONFORMATIONAL CHANGES 1
Chair: Randy Blakely & Klaus Bøgesø
Ulrik GETHER: Biophysical probing of biogenic amine transporters
Harald SITTE: Deciphering a role for oligomerization in neurotransmitter transporters
Carmen ARAGÓN: Glycine transporter 2: structure, function and subcellular localization
Session I: STRUCTURE, HETEROMERIC ASSEMBLY AND CONFORMATIONAL CHANGES 2
Chair: Gary Rudnick & Ulrik Gether
Jonathan A. JAVITCH: Oligomerization of the dopamine transporter: cocaine analogs alter the conformation of the dimer interface
Shimon SCHULDINER: Structural and functional probing of EmrE, a bacterial multidrug transporter
Peter MALONEY: The biochemistry and biophysics of OxlT, a member of the major facilitator superfamily
Ronald KABACK: The passion of permease
Session II: STRUCTURAL AND FUNCTIONAL PROBING OF GLUTAMATE TRANSPORTERS
Chair: Michael Robinson & Arne Schousboe
Susan AMARA: Ion conductances in neurotransmitter transporters
Baruch I. KANNER: Molecular characterization of the substrate binding pocket of glutamate transporters
Robert J. VANDENBERG: The chloride permeation pathway of a glutamate transporter and its proximity to the glutamate translocation domain
Niels Chr. DANBOLT: Cellular distribution and function of glutamate transporters
Farrukh A. CHAUDHRY: Transporter proteins involved in the recycling of the transmitter glutamate (Poster No. II-2)
Sonja M. WOJCIK: VGLUT expression levels as a source of variability in quantal size (Poster No. II-3)
Etienne HERZOG: Expression of vesicular glutamate transporters, VGLUT1 and VGLUT2, in cholinergic spinal motoneurons. (Poster No. II-4)
Session III: INTRACELLULAR TRANSPORTER SYSTEMS IN THE BRAIN
Chair: Heinrich Betz & Peter Høngaard Andersen
Robert EDWARDS: The transport of glutamate into synaptic vesicles
Bruno GIROS: Heterogeneity of glutamatergic neurons in the central nervous systems revealed by the distribution of vesicular glutamate transporter subtypes
Session IV: NEUROTRANSMITTER TRANSPORTERS: SCAFFOLDING, TARGETING AND TRAFFICKING
Chair: Robert Edwards & Niels Chr. Danbolt
Michael W. QUICK: Molecules in motion: Multiple mechanisms that regulate the GABA transporter GAT1
Randy BLAKELY: The resurfacing of the presynaptic choline transporter
Michael B. ROBINSON: Protein-protein interactions in glutamate transporter assembly and trafficking
Jeffrey D. ROTHSTEIN: Regulation and dysregulation of glutamate transporters by structure, localization and targeting
Gonzalo E. TORRES: Regulation of the dopamine transporter by interacting proteins (Poster No. IV-1)
Haley E. MELIKIAN: Constitutive and PKC-regulated catecholamine transporter internalization is mediated by two distinct and novel endocytic motifs (Poster No. IV-2)
L’Aurelle JOHNSON: Differential regulation of amphetamine-mediated dopamine release and binding to the dopamine transporter (DAT) by protein kinase C a and b isoforms (Poster No. IV-3)
Louis B. HERSH: Multiple sorting signals involved in the trafficking of the vesicular acetylcholine transporter (Poster No. IV-4)
Session V: NEUROTRANSMITTER TRANSPORTERS: PHARMACOLOGY AND STRUCTURE ACTIVITY STUDIES
Chair: Marc Caron
Arne SCHOUSBOE: Pharmacology and structure-activity relations of cloned as well as neuronal and glial GABA-transporters: Functional implications Klaus BØGESØ: SSRIs: Any room for improvement?
Session VI: NEUROTRANSMITTER TRANSPORTERS: PHYSIOLOGY AND DISEASE 1
Chair: Jeffrey D. Rothstein & Orla Miller Larsson
Heinrich BETZ: Physiological characterization and disease phenotypes of glycine transporter knockout mice
Isabelle M. MINTZ: Reversal of the DAT: physiological significance
Davide TROTTI: Glutamate transporters in disease
H. Steve WHITE: Modulation of GABA and glutamate transporter function: Implications for the treatment of epilepsy and other CNS disorders
Joseph B. JUSTICE: Localization of photoaffinity labeling sites of inhibitors at the human dopamine transporter (Poster No. VI-1)
Georgi GEGELASHVILI: Signal trandduction by glutamate transporters: Role of caspase-dependent truncation of cytoplasmic domains (Poster No. VI-7)
Howard GU: Do mice still like cocaine when their dopamine transporter is resistant to cocaine inhibition? (Poster No. VI-3)
Michael DIDRIKSEN: Antipsychotic potential of GlyT-1 inhibitors (Poster No. VI-4)