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Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity.

Trent J Volz1, M Kim, James O Schenk

  • 1Department of Chemistry, Washington State University, Pullman, Washington 99164, USA.

Synapse (New York, N.Y.)
|April 23, 2004
PubMed
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Arginine residues are crucial for dopamine transporter (DAT) function. Dopamine and cocaine interact with these arginine residues, suggesting potential for designing selective DAT inhibitors.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • The dopamine transporter (DAT) regulates dopamine levels in the brain.
  • Understanding DAT's molecular mechanisms is key for treating neurological disorders.
  • Arginine residues are implicated in protein function, but their role in DAT activity is not fully understood.

Purpose of the Study:

  • To investigate the role of arginine (Arg) residues in dopamine (DA) transporter (DAT) activity.
  • To determine if arginine-selective agents affect DA transport.
  • To examine if DA analogs and DAT inhibitors can modulate the effects of arginine-selective agents on DAT.

Main Methods:

  • Rotating disk electrode voltammetry was employed to measure DA transport.
  • Experiments were conducted using rat striatum and human embryonic kidney cells expressing rat DAT.

Related Experiment Videos

  • Arginine-selective agents, DA analogs, and various DAT inhibitors were utilized.
  • Main Results:

    • Phenylglyoxal (PG), an Arg-selective agent, decreased DA transport velocities.
    • Dopamine (DA) and its analogs (3-hydroxyphenethylamine, 4-hydroxyphenethylamine) attenuated PG's effects on DAT.
    • Cocaine and related tropane-based DAT inhibitors also attenuated PG's effects, unlike benztropine and GBR compounds.
    • Structure-activity studies indicated DA interacts via catechol hydroxyl groups and cocaine via an ester linkage with Arg residues.

    Conclusions:

    • Arginine residues are essential for DAT activity.
    • Dopamine and cocaine likely interact with the same critical Arg residue(s) on DAT.
    • Differential interactions of DAT inhibitors with Arg residues suggest possibilities for designing cocaine-activity-sparing antagonists.