Abstract
Serotonin transporters (SERTs), sites of psychostimulant action, display multiple conducting states in expression systems. These include a substrate-independent transient conductance, two separate substrate-independent leak conductances associated with Na(+) and H(+), and a substrate-dependent conductance of variable stoichiometry, which exceeds that predicted from electroneutral substrate transport. The present data show that the SNARE protein syntaxin 1A binds the N-terminal tail of SERT, and this interaction regulates two SERT-conducting states. First, substrate-induced currents are absent because Na(+) flux becomes strictly coupled to 5HT transport. Second, Na(+)-mediated leak currents are eliminated. These two SERT-conducting states are present endogenously in thalamocortical neurons, act to depolarize the membrane potential, and are modulated by molecules that disrupt SERT and syntaxin 1A interactions. These data show that protein interactions govern SERT activity and suggest that both cell excitability and psychostimulant-mediated effects will be dependent upon the state of association among SERT and its interacting partners.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Surface / metabolism*
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Binding Sites
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Botulinum Toxins, Type A / pharmacology
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cells, Cultured
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Choline / metabolism
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Cocaine / analogs & derivatives*
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Cocaine / metabolism
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Dose-Response Relationship, Drug
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Drug Interactions
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Electric Conductivity*
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Embryo, Mammalian
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Embryo, Nonmammalian
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Fluoxetine / pharmacology
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Humans
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Immunoblotting
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Isotope Labeling
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Kidney
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Transport Proteins*
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Microinjections
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Molecular Biology
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Munc18 Proteins
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Mutation
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N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
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Nerve Tissue Proteins / metabolism*
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Neurons / drug effects
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Neurons / physiology
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Oocytes
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Patch-Clamp Techniques / methods
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Peptide Fragments / pharmacology
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Proteins / pharmacology
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Radiopharmaceuticals / metabolism
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Rats
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / metabolism*
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Serotonin Agents / pharmacology
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Serotonin Plasma Membrane Transport Proteins
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Sodium / metabolism
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Syntaxin 1
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Thalamus / cytology
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Thalamus / metabolism
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Time Factors
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Tritium / metabolism
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Vesicular Transport Proteins*
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Xenopus laevis
Substances
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Antigens, Surface
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Carrier Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Munc18 Proteins
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Nerve Tissue Proteins
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Peptide Fragments
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Proteins
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Radiopharmaceuticals
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Recombinant Fusion Proteins
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SLC6A4 protein, human
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STX1A protein, human
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Serotonin Agents
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors
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Slc6a4 protein, rat
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Stx1a protein, rat
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Syntaxin 1
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Vesicular Transport Proteins
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Fluoxetine
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Tritium
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Serotonin
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2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
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Sodium
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Botulinum Toxins, Type A
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Cocaine
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N-Methyl-3,4-methylenedioxyamphetamine
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Choline