Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission.

Carvelli L, Blakely RD, DeFelice LJ
Proc Natl Acad Sci U S A. 2008 105 (37): 14192-7

PMID: 18768815 · PMCID: PMC2528871 · DOI:10.1073/pnas.0802214105

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 detectable 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.

MeSH Terms (13)

Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Dopamine Dopamine Plasma Membrane Transport Proteins Electrophysiology Genes, Reporter Patch-Clamp Techniques Protein Binding Recombinant Fusion Proteins Swimming Synaptic Transmission Syntaxin 1

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