Neurotransmitter sodium symporter

Last updated
Sodium:neurotransmitter symporter family
Identifiers
SymbolSNF
Pfam PF00209
InterPro IPR000175
PROSITE PDOC00533
SCOP2 2a65 / SCOPe / SUPFAM
TCDB 2.A.22
OPM superfamily 64
OPM protein 2a65
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the 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.

Contents

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.

Neurotransmitter sodium symporters (NSS) are targets for anti-depressants, psychostimulants and other drugs. [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 electrostatic interaction through adjacent binding sites. [9]

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

Related Research Articles

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

<span class="mw-page-title-main">Serotonin transporter</span> Mammalian protein found in humans

The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports the neurotransmitter serotonin from the synaptic cleft back to the presynaptic neuron, in a process known as serotonin reuptake.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

The sodium/phosphate cotransporter is a member of the phosphate:Na+ symporter (PNaS) family within the TOG Superfamily of transport proteins as specified in the Transporter Classification Database (TCDB).

<span class="mw-page-title-main">GABA transporter type 1</span> Protein-coding gene in the species Homo sapiens

GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the SLC6A1 gene and belongs to the solute carrier 6 (SLC6) family of transporters. It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.

<span class="mw-page-title-main">Sodium- and chloride-dependent glycine transporter 2</span> Protein-coding gene in the species Homo sapiens

Sodium- and chloride-dependent glycine transporter 2, also known as glycine transporter 2 (GlyT2), is a protein that in humans is encoded by the SLC6A5 gene.

An amino acid transporter is a membrane transport protein that transports amino acids. They are mainly of the solute carrier family.

<span class="mw-page-title-main">SLC6A14</span> Protein-coding gene in the species Homo sapiens

Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14) is a protein that in humans is encoded by the SLC6A14 gene.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

GABA transporters (Gamma-Aminobutyric acid transporters) belong to the family of neurotransmitters known as sodium symporters, also known as solute carrier 6 (SLC6). These are large family of neurotransmitter which are Na+ concentration dependent. They are found in various regions of the brain in different cell types, such as neurons and astrocytes.

<span class="mw-page-title-main">Sodium-solute symporter</span> Group of transport proteins

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na+ symport.

<span class="mw-page-title-main">Sodium:dicarboxylate symporter</span> Protein family

It has been shown that integral membrane proteins that mediate the uptake of a wide variety of molecules with the concomitant uptake of sodium ions can be grouped, on the basis of sequence and functional similarities into a number of distinct families. One of these families is known as the sodium:dicarboxylate symporter family (SDF).

<span class="mw-page-title-main">Bacterial Leucine Transporter</span>

Bacterial Leucine Transporter (LeuT) is a bundled twelve alpha helix protein which belongs to the family of transporters that shuttle amino acids in and out of bacterial cells. Specialized in small hydrophobic amino acids such as leucine and alanine, this transporter is powered by the gradient of sodium ions that is normally maintained by healthy cells across their membranes. LeuT acts as a symporter, which means that it links the passage of a sodium ion across the cell membrane with the transport of the amino acid in the same direction. It was first crystallized to understand the inner molecular mechanisms of antidepressant's work since it has a close resemblance with the human neurotransmitter transporters that these drugs block, thus inhibiting the reuptake of chemical messengers across the cell membrane of nerve axons and glial cells.

The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number. This superfamily has since been expanded to include eighteen different families.

The branched chain amino acid:cation symporter (LIVCS) family (TC# 2.A.26) is a member of the APC superfamily. Characterized members of this family transport all three of the branched chain aliphatic amino acids (leucine (L), isoleucine (I) and valine (V)). These proteins are found in Gram-negative and Gram-positive bacteria and function by a Na+ or H+ symport mechanism. They possess about 440 amino acyl residues and display 12 putative transmembrane helical spanners. As of early 2016, no crystal structures for members of the LIVCS family are available on RCSB.

The ion transporter (IT) superfamily is a superfamily of secondary carriers that transport charged substrates.

Proton-coupled amino acid transporters belong to the SLC26A5 family; they are protein receptors whose main function is the transmembrane movement of amino acids and their derivatives. This family of receptors is most commonly found within the luminal surface of the small intestine as well as in some lysosomes. The solute carrier family (SLC) of genes includes roughly 400 membrane proteins that are characterized by 66 families in total. The SLC36 family of genes maps to chromosome 11. The diversity of these receptors is vast, with the ability to transport both charged and uncharged amino acids along with their derivatives. In research and practice, SLC36A1/2 are both targets for drug-based delivery systems for a wide range of disorders.

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" (PDF). Pflügers Archiv. 466 (1): 25–42. doi:10.1007/s00424-013-1410-1. PMC   3930102 . PMID   24337881.
  2. 1 2 3 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. S2CID   2334406.
  4. ↑ 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. Bibcode:2007Natur.449..726Z. doi: 10.1038/nature06133 . PMID   17704762. S2CID   4391735.
  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. S2CID   41721766.
  7. ↑ Uhl GR, Johnson PS (1994). "Neurotransmitter transporters: three important gene families for neuronal function". J. Exp. Biol. 196: 229–236. doi:10.1242/jeb.196.1.229. PMID   7823024.
  8. ↑ Nelson N, Lill H (1998). "Homologies and family relationships among Na+/Cl− neurotransmitter transporters". Neurotransmitter Transporters. Methods in Enzymology. Vol. 296. pp. 425–436. doi:10.1016/S0076-6879(98)96030-X. ISBN   978-0-12-182197-5. PMID   9779464.{{cite book}}: |journal= ignored (help)
  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   3024779 . PMID   21115480.
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