Skip to main content
SpringerLink
Log in

Structure and Function of GABA Transporters

  • Chapter
Book cover Pharmacology of GABA and Glycine Neurotransmission

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 150))

Abstract

Neurotransmitters are transported across two types of membranes:

  1. 1.

    Plasma membranes of nerve endings (presynaptic), dendrites (postsynaptic) and glial cells (see Kanner and Schuldiner 1987; Palacin et al. 1998 for reviews)

  2. 2.

    Membranes of intracellular storage organelles (see Schuldiner et al. 1995 for a review)

Transport into storage organelles is powered by the electrochemical proton gradient and does not require sodium. Its major function is to concentrate the neurotransmitter from the cytoplasm into the storage organelles in preparation for exocytotic release. In addition to the family of vesicular transporters for biogenic amines and acetylcholine (Schuldiner et al. 1995), recently the first member of a new family of vesicular transporters — carrying GABA and glycine — has been cloned (Mclntire et al. 1997; Sagne etal.1997).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Barker EL, Moore KR, Rakhshan F, Blakely RD (1999) Transmembrane domain I contributes to the permeation pathway for serotonin and ions in the serotonin transporter. J Neurosci 19:4705–4717

    PubMed  CAS  Google Scholar 

  • Bendahan A, Kanner BI (1993) Identification of domains of a cloned rat brain GABA transporter which are not required for its functional expression. FEBS Lett 318:41–44

    Article  PubMed  CAS  Google Scholar 

  • Bennett ER, Kanner BI (1997) The membrane topology of GAT-1, a (Na+-CL)-coupled γ-aminobutyric acid transporter from brain. J Biol Chem 272:1203–1210

    Article  PubMed  CAS  Google Scholar 

  • Bismuth Y, Kavanaugh MP, Kanner BI (1997) Tyrosine 140 of the γ-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition. J Biol Chem 272:16046–16102

    Article  Google Scholar 

  • Blakely RD, Benson HE, Fremeau RT Jr, Caron MG, Peek MM, Prince HK, Bradley CC (1991) Cloning and expression of a functional serotonin transporter from rat brain. Nature 353:66–70

    Article  Google Scholar 

  • Borden LA, Smith KE, Hartig PR, Branchek TA, Weinshank RL (1992) Molecular heterogeneity of the GABA transport system. J Biol Chem 267:21098–21104

    PubMed  CAS  Google Scholar 

  • Chen JG, Chen SL, Rudnick G (1998) Determination of external loop topology in the serotonin transporter by site-directed chemical labeling. J Biol Chem 273:12675–12681

    Article  PubMed  CAS  Google Scholar 

  • Clark JA, Deutch AY, Gallipoli PZ, Amara SG (1992) Functional expression and CNS distribution of a ß-alanine sensitive neuronal GABA transporter. Neuron 9:337–348

    Article  PubMed  CAS  Google Scholar 

  • Fremeau RT Jr, Caron MG, Blakely RD (1992) Molecular cloning and expression of a high affinity 1-proline transporter expressed in putative glutamatergic pathways of rat brain. Neuron 8:915–926

    Article  PubMed  CAS  Google Scholar 

  • Giros B, Jaber M, Jones SR, Wightman RM and Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612

    Article  PubMed  CAS  Google Scholar 

  • Golovanevsky V, Kanner BI (1999) The reactivity of the γ-aminobutyric acid transporter GAT-1 is conformationally sensitive. Identification of a major target residue. J Biol Chem 274:23020–23026

    Article  PubMed  CAS  Google Scholar 

  • Guastella J, Brecha N, Weigmann C, Lester HA (1992) Cloning, expression and localization of a rat brain high affinity glycine transporter. Proc Natl Acad Sci, USA 89:7189–7193

    Article  PubMed  CAS  Google Scholar 

  • Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson NC, Lester HA, Kanner BI (1990) Cloning and expression of a rat brain GABA transporter. Science 249:1303–1306

    Article  PubMed  CAS  Google Scholar 

  • Guimbal C, Kilimann MW (1993) A Na+ dependent creatine transporter in rabbit brain, muscle, heart and kidney. cDNA cloning and functional expression. J Biol Chem 268:8418–8421

    PubMed  CAS  Google Scholar 

  • Hoffman BJ, Mezey E, Brownstein MJ (1991) Cloning of a serotonin transporter affected by antidepressants. Science 254:579–580

    Article  PubMed  CAS  Google Scholar 

  • Kanner BI (1993) Glutamate transporters from brain: a novel neurotransmitter transporter family. FEBS Lett 325:95–99

    Article  PubMed  CAS  Google Scholar 

  • Kanner BI, Bendahan A, Pantanowitz S, Su H (1994) The number of amino acid residues in hydrophilic loops connecting transmembrane domains of the GABA transporter GAT-1 is critical for its function. FEBS Lett 356:191–194

    Article  PubMed  CAS  Google Scholar 

  • Kanner BI, Keynan S, Radian R (1989) Structural and functional studies on the sodium- and chloride-coupled γ-aminobutyric acid transporter. Deglycosylation and limited proteolysis. Biochemistry 28:3722–3727

    Article  PubMed  CAS  Google Scholar 

  • Kanner BI, Schuldiner S (1987) Mechanism of transport and storage of neurotransmitters. CRC Crit Rev Biochem 22:1–39

    Article  PubMed  CAS  Google Scholar 

  • Kavanaugh MP, Arriza JL, North RA, Amara SG (1992) Electrogenic uptake of γ-aminobutyric acid by a cloned transporter expressed in oocytes. J Biol Chem 267:22007–22009

    PubMed  CAS  Google Scholar 

  • Keshet GI, Bendahan A, Su H, Mager S, Lester HA, Kanner BI (1995) Glutamate-101 is critical for the function of the sodium and chloride-coupled GABA transporter GAT-1. FEBS Lett 371:39–42

    Article  PubMed  CAS  Google Scholar 

  • Keynan S, Kanner BI (1988) γ-Aminobutyric acid transport in reconstituted preparations from rat brain: coupled sodium and chloride fluxes. Biochemistry 27:12–17

    Article  PubMed  CAS  Google Scholar 

  • Keynan S, Suh Y-J, Kanner BI, Rudnick G (1992) Expression of a cloned γ-aminobutyric acid transporter in mammalian cells. Biochemistry 31:1974–1979

    Article  PubMed  CAS  Google Scholar 

  • Kilty JE, Lorang D, Amara SG (1991) Cloning and expression of a cocaine-sensitive rat dopamine transporter. Science 254:578–579

    Article  PubMed  CAS  Google Scholar 

  • Kitayama S, Shimada S, Xu H, Markham L, Donovan DM, Uhl GR (1992) Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. Proc Natl Acad Sci USA 89:7782–7785

    Article  PubMed  CAS  Google Scholar 

  • Kleinberger-Doron N, Kanner BI (1994) Identification of tryptophan residues critical for the function and targeting of the γ-aminobutyric acid transporter (subtype A). J Biol Chem 269:3063–3067

    PubMed  CAS  Google Scholar 

  • Kuhar MJ, Zarbin MA (1978) Synaptosomal transport: a chloride dependence for choline, GABA, glycine and several other compounds. J Neurochem 31:251–256

    Article  PubMed  CAS  Google Scholar 

  • Liu QR, Lopez-Corcuera B, Mandiyan S, Nelson H, Nelson N (1993a) Molecular characterization of four pharmacologically distinct γ-aminobutyric acid transporters in mouse brain. J Biol Chem 268:2104–2112

    Google Scholar 

  • Liu QR, Lopez-Corcuera B, Nelson H, Mandiyan S, Nelson N (1992a) Cloning and expression of a cDNA encoding the transporter of taurine and γ-alanine in mouse brain. Proc Natl Acad Sci USA 89:12145–12149

    Article  PubMed  CAS  Google Scholar 

  • Liu QR, Mandiyan S, Lopez-Corcuera B, Nelson H, Nelson N (1993b) A rat brain cDNA encoding the neurotransmitter transporter with an unusual structure. FEBS Lett 315:114–118

    Article  PubMed  CAS  Google Scholar 

  • Liu QR, Nelson H, Mandiyan S, Lopez-Corcuera B, Nelson N (1992b) Cloning and expression of a glycine transporter from mouse brain. FEBS Lett 305:110–114

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Corcuera B, Liu QR, Mandiyan S, Nelson H, Nelson N (1992) Expression of a mouse brain cDNA encoding novel γ-aminobutyric acid transporter. J Biol Chem 267:17491–17493

    PubMed  CAS  Google Scholar 

  • Lopez-Corcuera B, Vazquez J, Aragon C (1991) Purification of the sodium- and chloride-coupled glycine transporter from central nervous system. J Biol Chem 266:24809–24814

    PubMed  CAS  Google Scholar 

  • Mabjeesh NJ, Kanner, BI (1992) Neither amino nor carboxyl termini are required for function of the sodium- and chloride-coupled γ-aminobutyric acid transporter from rat brain. J Biol Chem 267:2563–2568

    PubMed  CAS  Google Scholar 

  • Mabjeesh NJ, Kanner BI (1993) The substrates of a sodium- and chloride-coupled γ-aminobutyric acid transporter protect multiple sites throughout the protein against proteolytic cleavage. Biochemistry 32:8540–8546

    Article  PubMed  CAS  Google Scholar 

  • Mager S, Kleinberger-Doron N, Keshet, GI, Davidson N, Kanner BI, Lester HA (1996) Ion binding and permeation at the GABA transporter GAT-1. J Neurosci 16:5405–5414

    PubMed  CAS  Google Scholar 

  • Mager S, Naeve J, Quick M, Labarca C, Davidson N, Lester HA (1993) Steady states, charge movements and rates for a cloned GABA transporter expressed in Xenopus oocytes. Neuron 10:177–188

    Article  PubMed  CAS  Google Scholar 

  • Mclntire SL, Reimer RJ, Schuski K, Edwards RH, Jorgensen IM (1997) Identification and characterization of the vesicular GABA transporter. Nature 389:870–876

    Article  Google Scholar 

  • Olivares L, Aragon C, Gimenez C, Zafra F (1997) Analysis of the transmembrane topology of the glycine transporter GlyTl. J Biol Chem 272:1211–1217

    Article  PubMed  CAS  Google Scholar 

  • Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine and antidepressant-sensitive human noradrenaline transporter. Nature 350:350–354

    Article  PubMed  CAS  Google Scholar 

  • Palacin M, Estevez R, Bertan J, Zorzano A (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 78:969–1054

    PubMed  CAS  Google Scholar 

  • Pantanowitz S, Bendahan A, Kanner BI (1993) Only one of the charged amino acids located in the transmembrane a helices of the γ-aminobutyric acid transporter (subtype A) is essential for its activity. J Biol Chem 268:3222–3225

    PubMed  CAS  Google Scholar 

  • Radian R, Bendahan A, Kanner BI (1986) Purification and identification of the functional sodium- and chloride-coupled γ-aminobutyric acid transport glycoprotein from rat brain. J Biol Chem 261:15437–15441

    PubMed  CAS  Google Scholar 

  • Radian R, Kanner BI (1983) Stoichiometry of sodium- and chloride-coupled γ-aminobutyric acid transport by synaptic plasma membrane vesicles isolated from rat brain. Biochemistry 22:1236–1241

    Article  PubMed  CAS  Google Scholar 

  • Radian R, Kanner, BI (1985) Reconstitution and purification of the sodium- and chloride-coupled γ-aminobutyric acid transporter from rat brain. J Biol Chem 260:11859–11865

    PubMed  CAS  Google Scholar 

  • Sagne C, El-Mestikawy S, Isembert MF, Hamon M, Henry JP, Giros B and Gasnier B (1997) Cloning of a functional vesicular GABA and glycine transporter by screening of genomic databases. FEBS Lett 412:177–183

    Article  Google Scholar 

  • Schuldiner S, Shirvan A, Linial M (1995) Vesicular neurotransmitters: from bacteria to humans. Physiol Rev 75:369–392

    PubMed  CAS  Google Scholar 

  • Shimada S, Kitayama S, Lin CL, Patel A, Nanthakumar E, Gregor P, Kuhar M, Uhl G (1991) Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA. Science 254:576–578

    Article  PubMed  CAS  Google Scholar 

  • Smith KE, Borden LA, Hartig PA, Branchek T, Weinshank RL (1992) Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8:927–935

    Article  PubMed  CAS  Google Scholar 

  • Sussman JL, Silman I (1992) Acetylcholinesterase: structure and use as a model for specific cation-protein interactions. Curr Opin Struc Biol 2:721–729

    Article  CAS  Google Scholar 

  • Tamura S, Nelson H, Tamura A, Nelson N (1995) Short external loops as potential substrate binding site of γ-aminobutyric acid transporters. J Biol Chem 270: 28712–28715

    Article  PubMed  CAS  Google Scholar 

  • Uchida S, Kwon HM, Yamauchi A, Preston AS, Marumo F, Handler JS (1992) Molecular cloning of the cDNA for an MDCK cell Na+- and Cl--dependent taurine transporter that is regulated by hypertonicity. Proc Natl Acad Sci, USA 89:8230–8234

    Article  PubMed  CAS  Google Scholar 

  • Uhl GR (1992) Neurotransmitters (plus): a promising new gene family. Trends Neurosci 15:265–285

    Article  PubMed  CAS  Google Scholar 

  • Uhl GR, Kitayama S, Gregor P, Nanthakumer E, Persico A, Shimada S (1992) Neurotransmitter transporter family cDNAs, in a rat midbrain library: ’orphan transporters’ suggest sizable structural variations. Molec Brain Res 16:353–359

    Article  PubMed  CAS  Google Scholar 

  • Usdin TB, Mezey E, Chen C, Brownstein MJ, Hoffman BJ (1991) Cloning of the cocaine sensitive bovine dopamine transporter. Proc Natl Acad Sci USA 88:11168–11171

    Article  PubMed  CAS  Google Scholar 

  • Yamauchi A, Uchida S, Kwon HM, Preston AS, Robey RB, Garcia-Perez A, Burg MB, Handler JS (1992) Cloning of a Na+ and CI- dependent betaine transporter that is regulated by hypertonicity. J Biol Chem 267:649–652

    PubMed  CAS  Google Scholar 

  • Yu N, Cao Y, Mager S, Lester HA (1998) Topological localization of cysteine 74 in the GABA transporter, GAT-1, and its importance in ion binding and permeation. FEBS Lett 426:174–178

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. B. I. Kanner
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Pharmacology and Toxicology, ETH and University of Zürich, Winterthurerstr. 190, CH-8057, Zürich, Switzerland

    Hanns Möhler

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kanner, B.I. (2001). Structure and Function of GABA Transporters. In: Möhler, H. (eds) Pharmacology of GABA and Glycine Neurotransmission. Handbook of Experimental Pharmacology, vol 150. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56833-6_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-56833-6_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63191-7

  • Online ISBN: 978-3-642-56833-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation