Benzon Symposium No. 51
Neurotransmitter
Transporters: Basal Function and Drug Targets
August 9-12, 2004
Copenhagen,
Denmark
Organizing Committee: Ulrik Gether, Orla Miller Larsson, Peter Høngaard Andersen,
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)
Session
VI: NEUROTRANSMITTER TRANSPORTERS: PHYSIOLOGY AND DISEASE 2
Chair:
Susan Amara & Sven Frøkjær
Gary
RUDNICK:
Serotonin transporter: Structure, function and regulation
Bertha
MADRAS: Genetic
variation and transporter pharmacology
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