Zn2+ modulation of neurotransmitter transporters.
Neurotransmitter transporters located at the presynaptic or glial cell membrane are responsible for the stringent and rapid clearance of the transmitter from the synapse, and hence they terminate signaling and control the duration of synaptic inputs in the brain. Two distinct families of neurotransmitter transporters have been identified based on sequence homology: (1) the neurotransmitter sodium symporter family (NSS), which includes the Na+/C1(-)-dependent transporters for dopamine, norepinephrine, and serotonin; and (2) the dicarboxylate/amino acid cation symporter family (DAACS), which includes the Na(+)-dependent glutamate transporters (excitatory amino acid transporters; EAAT). In this chapter, we describe how the identification of endogenous Zn2(+)-binding sites, as well as engineering of artificial Zn2(+)-binding sites both in the Na+/Cl(-)-dependent transporters and in the EAATs, have proved to be an important tool for studying the molecular function of these proteins. We also interpret the current available data on Zn2(+)-binding sites in the context of the recently published crystal structures. Moreover, we review how the identification of endogenous Zn2(+)-binding sites has indirectly suggested the possibility that several of the transporters are modulated by Zn2+ in vivo, and thus that Zn2+ can play a role as a neuromodulator by affecting the function of neurotransmitter transporters.
Nørgaard-Nielsen
K
K
Molecular Neuropharmacology Group, Department of Pharmacology, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
Gether
U
U
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D050479:Neurotransmitter Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D011487:Protein Conformation; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D050491:Glutamate Plasma Membrane Transport Proteins; D050487:Glycine Plasma Membrane Transport Proteins; D050479:Neurotransmitter Transport Proteins; D015032:Zinc