Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission
- 16 September 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (37), 14192-14197
- https://doi.org/10.1073/pnas.0802214105
Abstract
The Caenorhabditis elegans (C. elegans) dopamine (DA) transporter (DAT-1) regulates DA signaling through efficient DA reuptake following synaptic release. In addition to its DA transport function, DAT-1 generates detectible DA-gated currents that may influence neuronal excitability. Previously, we provided evidence that single Cl-channel events underlie DAT-1 currents. In these studies, we identified a distinct population of altered DAT-1 currents arising from DAT-1 transgenic constructs bearing an N-terminal GFP fusion. The presence of these channels suggested disruption of an endogenous regulatory mechanism that modulates occupancy of DAT-1 channel states. A leading candidate for such a regulator is the SNARE protein syntaxin 1A (Syn1A), previously found to interact with homologous transporters through N-terminal interactions. Here we establish that UNC-64 (C. elegans Syn1A homologue) associates with DAT-1 and suppresses transporter channel properties. In contrast, GFP::DAT-1 is unable to form stable transporter/UNC-64 complexes that limit channel states. Although DAT-1 and GFP::DAT-1 expressing DA neurons exhibit comparable DA uptake, GFP::DAT-1 animals exhibit swimming-induced paralysis (SWIP), a phenotype associated with excess synaptic DA release and spillover. We propose that loss of UNC-64/DAT-1 interactions leads to enhanced synaptic DA release, providing a novel mechanism for DA neuron sensitization that may be relevant to mechanisms of DA-associated disorders.Keywords
This publication has 27 references indexed in Scilit:
- Vigorous Motor Activity inCaenorhabditis elegansRequires Efficient Clearance of Dopamine Mediated by Synaptic Localization of the Dopamine Transporter DAT-1Journal of Neuroscience, 2007
- GABA Transporter Currents Activated by Protein Kinase A Excite Midbrain Neurons during Opioid WithdrawalNeuron, 2005
- The Human Dopamine Transporter Forms a Tetramer in the Plasma MembraneJournal of Biological Chemistry, 2003
- Regulating the Conducting States of a Mammalian Serotonin TransporterNeuron, 2003
- C. elegans: des neurones et des gènesmédecine/sciences, 2003
- Oligomerization and Trafficking of the Human Dopamine TransporterPublished by Elsevier BV ,2003
- Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporterNature, 1996
- Functional impact of syntaxin on gating of N-type and Q-type calcium channelsNature, 1995
- The synaptic vesicle cycle: a cascade of protein–protein interactionsNature, 1995
- Cloning, sequencing, and mapping of an α‐actinin gene from the nematode Caenorhabditis elegansCell Motility, 1991