TY - JOUR

T1 - Probing dopamine transporter structure and function by Zn2+-site engineering

AU - Loland, Claus Juul

AU - Norgaard-Nielsen, Kristine

AU - Gether, Ulrik

PY - 2003/10/31

Y1 - 2003/10/31

N2 - The biogenic amine transporters belong to the class of Na+/Cl--coupled solute carriers and include the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT). These transporters are the primary targets for the action of many psychoactive compounds including the most commonly used antidepressants as well as widely abused drugs such as cocaine and amphetamines. In spite of their pharmacological importance, still little is known about their higher structural organization and the molecular mechanisms underlying the substrate translocation process. In this review, it will be described how we have used Zn2+-binding sites as a tool to probe the structure and function of Na+/Cl--coupled biogenic amine transporters with specific focus on the human DAT (hDAT). The work has not only led to the definition of the first structural constrains in the tertiary structure of this class of transporters, but also allowed inferences about conformational changes accompanying substrate translocation and residues critical for regulating the equilibrium between different functional states in the transport cycle.

AB - The biogenic amine transporters belong to the class of Na+/Cl--coupled solute carriers and include the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT). These transporters are the primary targets for the action of many psychoactive compounds including the most commonly used antidepressants as well as widely abused drugs such as cocaine and amphetamines. In spite of their pharmacological importance, still little is known about their higher structural organization and the molecular mechanisms underlying the substrate translocation process. In this review, it will be described how we have used Zn2+-binding sites as a tool to probe the structure and function of Na+/Cl--coupled biogenic amine transporters with specific focus on the human DAT (hDAT). The work has not only led to the definition of the first structural constrains in the tertiary structure of this class of transporters, but also allowed inferences about conformational changes accompanying substrate translocation and residues critical for regulating the equilibrium between different functional states in the transport cycle.

KW - Amino Acid Sequence

KW - Animals

KW - Binding Sites

KW - Dopamine Plasma Membrane Transport Proteins

KW - Dose-Response Relationship, Drug

KW - Humans

KW - Membrane Glycoproteins

KW - Membrane Transport Proteins

KW - Molecular Sequence Data

KW - Nerve Tissue Proteins

KW - Protein Conformation

KW - Protein Engineering

KW - Structure-Activity Relationship

KW - Zinc

M3 - Journal article

C2 - 14612149

VL - 479

SP - 187

EP - 197

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1-3

ER -