Neurotransmitter sodium symporter

Sodium:neurotransmitter symporter family
Identifiers
Symbol SNF
Pfam PF00209
InterPro IPR000175
PROSITE PDOC00533
SCOP 2a65
SUPERFAMILY 2a65
TCDB 2.A.22
OPM superfamily 67
OPM protein 2a65

Members of the Neurotransmitter:Sodium Symporter (NSS) family (TC# 2.A.22) catalyze uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism.[1][2] The NSS family is a member of the APC Superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

Function

Neurotransmitter transport systems are responsible for the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal, from the extracellular space, of released-transmitters, thereby terminating their actions.[3]

The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na+ and Cl−, in order to transport neurotransmitter molecules into the cell against their concentration gradient.

Since neurotransmitter:sodium symporters (NSS) have a critical role in regulating neurotransmission, they are targets for psychostimulants, anti-depressants and other drugs. In eukaryotic NSS, chloride is transported together with the neurotransmitter. However, transport by the bacterial homologues LeuT, Tyt1 and TnaT is chloride-independent. The crystal structure of LeuT (3F3A​) reveals an occluded binding pocket containing leucine and two sodium ions. Zomot et al., (2007) found that introduction of a negatively charged amino acid at or near one of the two putative sodium-binding sites of the GABA (γ-aminobutyric acid) transporter GAT-1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride-independent.[4] In contrast to wild-type GAT-1, a marked stimulation of the rate of net flux (but not of exchange) was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11) and the human dopamine transporter DAT (SLC6A3) also resulted in chloride-independent transport. The reciprocal mutations in LeuT and Tyt1 rendered substrate binding and/or uptake by these bacterial NSS chloride-dependent. Zomot et al.'s data indicated that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the co-transported sodium ions.[2][4]

Transport Reaction

The generalized transport reaction for the members of this family is:[2]

solute (out) + Na+ (out) → solute (in) + Na+ (in).

Structure

The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine, taurine and other small molecules.[2]

NSS carriers are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport (see TC# 2.A.23). The latter couple glutamate and aspartate uptake to the cotransport of Na+ and the counter-transport of K+, with no apparent dependence on Cl−.[5] In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters.[6][7] Sequence analysis of the Na+/Cl− neurotransmitter superfamily reveals that it can be divided into four subfamilies, these being transporters for monoamines, the amino acids proline and glycine, GABA, and a group of orphan transporters.[8]

Tavoulari et al. (2011) described conversion of the Cl− -independent prokaryotic tryptophan transporter TnaT (2.A.22.4.1) to a fully functional Cl− -dependent form by a single point mutation, D268S. Mutations in TnaT-D268S, in wild type TnaT and in a serotonin transporter (SERT; 2.A.22.1.1) provided direct evidence for the involvement of each of the proposed residues in Cl− coordination. In both SERT and TnaT-D268S, Cl− and Na+ mutually increase each other's potency, consistent with am electrostatic interaction through adjacent binding sites.[9]

The crystal structure of a bacterial member of the NSS family has been determined complexed to leucine and 2 Na+.[10] The protein core consists of the first ten of the 12 TMSs with segments 1-5 and 6-10 exhibiting a pseudo-2-fold axis of symmetry in the plane of the membrane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The binding pocket of LeuT contains two metal binding sites.[11] The first ion in site NA1 is directly coupled to the bound substrate (Leu) with the second ion in the neighboring site (NA2) approximately 7 Å away. Double ion occupancy of the binding pocket is required to ensure substrate coupling to Na+ (but not to Li+ or K+ cations). The presence of the ion in site NA2 is required for structural stability of the binding pocket as well as amplified selectivity for Na+ in the case of double ion occupancy.[11]

Crystal Structures

There are several crystal structures available for a couple members of the NSS family:

Subfamilies

Several characterized proteins are classified within the NSS family and can be found in the Transporter Classification Database.

Human proteins containing this domain

SLC6A1, SLC6A2, SLC6A3, SLC6A4, SLC6A5, SLC6A6, SLC6A7, SLC6A8, SLC6A9, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19, SLC6A20

See also

References

  1. ↑ Rudnick, G; Krämer, R; Blakely, RD; Murphy, DL; Verrey, F (January 2014). "The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction.". Pflugers Archive. 466 (1): 25–42. doi:10.1007/s00424-013-1410-1. PMC 3930102Freely accessible. PMID 24337881.
  2. 1 2 3 4 Saier, MH Jr. "2.A.22 The Neurotransmitter:Sodium Symporter (NSS) Family". Transporter Classification Database.
  3. ↑ Attwell D, Bouvier M (1992). "Cloners quick on the uptake". Curr. Biol. 2 (10): 541–543. doi:10.1016/0960-9822(92)90024-5. PMID 15336049.
  4. 1 2 Zomot, E; Bendahan, A; Quick, M; Zhao, Y; Javitch, JA; Kanner, BI (October 11, 2007). "Mechanism of chloride interaction with neurotransmitter:sodium symporters.". Nature. 449 (7163): 726–30. doi:10.1038/nature06133. PMID 17704762.
  5. ↑ Malandro MS, Kilberg MS (1996). "Molecular biology of mammalian amino acid transporters". Annu. Rev. Biochem. 65: 305–336. doi:10.1146/annurev.bi.65.070196.001513. PMID 8811182.
  6. ↑ Arriza JL, Amara SG (1993). "Neurotransmitter transporters: three distinct gene families". Curr. Opin. Neurobiol. 3 (3): 337–344. doi:10.1016/0959-4388(93)90126-J. PMID 8103691.
  7. ↑ Uhl GR, Johnson PS (1994). "Neurotransmitter transporters: three important gene families for neuronal function". J. Exp. Biol. 196: 229–236. PMID 7823024.
  8. ↑ Nelson N, Lill H (1998). "Homologies and family relationships among Na+/Cl− neurotransmitter transporters". Meth. Enzymol. Methods in Enzymology. 296: 425–436. doi:10.1016/S0076-6879(98)96030-X. ISBN 978-0-12-182197-5. PMID 9779464.
  9. ↑ Tavoulari, S; Rizwan, AN; Forrest, LR; Rudnick, G (January 28, 2011). "Reconstructing a chloride-binding site in a bacterial neurotransmitter transporter homologue.". Journal of Biological Chemistry. 286 (4): 2834–42. doi:10.1074/jbc.M110.186064. PMC 3024779Freely accessible. PMID 21115480.
  10. ↑ Yamashita, A; Singh, SK; Kawate, T; Jin, Y; Gouaux, E (September 8, 2005). "Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.". Nature. 437 (7056): 215–23. doi:10.1038/nature03978. PMID 16041361.
  11. 1 2 Caplan, DA; Subbotina, JO; Noskov, SY (November 15, 2008). "Molecular mechanism of ion-ion and ion-substrate coupling in the Na+-dependent leucine transporter LeuT.". Biophysical Journal. 95 (10): 4613–21. doi:10.1529/biophysj.108.139741. PMC 2576368Freely accessible. PMID 18708457.
This article is issued from Wikipedia - version of the 7/14/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.