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Br J Pharmacol
2013 Feb 01;1684:891-902. doi: 10.1111/j.1476-5381.2012.02213.x.
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Oleoyl-L-carnitine inhibits glycine transport by GlyT2.
Carland JE
,
Mansfield RE
,
Ryan RM
,
Vandenberg RJ
.
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Concentrations of extracellular glycine in the CNS are regulated by two Na(+)/Cl(-) -dependent glycine transporters, GlyT1 and GlyT2. Selective inhibitors of GlyT1 have been developed for the treatment of schizophrenia, whilst selective inhibitors of GlyT2 are analgesic in animal models of pain. We have assessed a series of endogenous lipids as inhibitors of GlyT1 and GlyT2. Human GlyT1 and GlyT2 were expressed in Xenopus laevis oocytes, and the inhibitory actions of a series of acylcarnitines on glycine transport were measured using electrophysiological techniques. Oleoyl-L-carnitine inhibited glycine transport by GlyT2, with an IC(50) of 340 nM, which is 15-fold more potent than the previously identified lipid inhibitor N-arachidonyl-glycine. Oleoyl-L-carnitine had a slow onset of inhibition and a slow washout. Using a series of chimeric GlyT1/2 transporters and point mutant transporters, we have identified an isoleucine residue in extracellular loop 4 of GlyT2 that conferred differences in sensitivity to oleoyl-L-carnitine between GlyT2 and GlyT1. Oleoyl-L-carnitine is a potent non-competitive inhibitor of GlyT2. Previously identified GlyT2 inhibitors show potential as analgesics and the identification of oleoyl-L-carnitine as a novel GlyT2 inhibitor may lead to new ways of treating pain.
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011, Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed
Andersen,
Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants.
2009,
Pubmed
Atkinson,
ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter.
2001,
Pubmed
Aubrey,
N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) is a selective persistent inhibitor of glycine transport.
2001,
Pubmed
,
Xenbase
Bradbury,
Molecular modeling and functional confirmation of a predicted fatty acid binding site of mitochondrial aspartate aminotransferase.
2011,
Pubmed
Chattopadhyay,
Fluorimetric determination of critical micelle concentration avoiding interference from detergent charge.
1984,
Pubmed
Chiechio,
L-Acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors.
2002,
Pubmed
Cho,
Studies on the mechanism of hemolysis by acyl carnitines, lysolecithins and acyl cholines.
1971,
Pubmed
Connor,
N-acyl amino acids and N-acyl neurotransmitter conjugates: neuromodulators and probes for new drug targets.
2010,
Pubmed
Doi,
Absorption enhancement effect of acylcarnitines through changes in tight junction protein in Caco-2 cell monolayers.
2011,
Pubmed
Edington,
Extracellular loops 2 and 4 of GLYT2 are required for N-arachidonylglycine inhibition of glycine transport.
2009,
Pubmed
,
Xenbase
Eulenburg,
Glycine transporters: essential regulators of neurotransmission.
2005,
Pubmed
Fix,
Acylcarnitines: drug absorption-enhancing agents in the gastrointestinal tract.
1986,
Pubmed
Foster,
The role of the carnitine system in human metabolism.
2004,
Pubmed
Gasbarri,
Fine-tuning of POPC liposomal leakage by the use of beta-cyclodextrin and several hydrophobic guests.
2010,
Pubmed
Jeong,
N-arachidonyl-glycine modulates synaptic transmission in superficial dorsal horn.
2010,
Pubmed
Jones,
Acylcarnitines: role in brain.
2010,
Pubmed
Ju,
Zn2+ inhibits glycine transport by glycine transporter subtype 1b.
2004,
Pubmed
,
Xenbase
Kim,
Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes.
1994,
Pubmed
Kinney,
The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior.
2003,
Pubmed
Krishnamurthy,
X-ray structures of LeuT in substrate-free outward-open and apo inward-open states.
2012,
Pubmed
LeCluyse,
Relationship between drug absorption enhancing activity and membrane perturbing effects of acylcarnitines.
1991,
Pubmed
Lechner,
Glutamate-based therapeutic approaches: inhibitors of glycine transport.
2006,
Pubmed
Liu,
Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features.
1993,
Pubmed
,
Xenbase
Liu,
Glycine transporter 1 associates with cholesterol-rich membrane raft microdomains.
2009,
Pubmed
Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed
Pantano,
Characterization of membrane-protein interactions for the leucine transporter from Aquifex aeolicus by molecular dynamics calculations.
2009,
Pubmed
Pearlman,
Arachidonic acid and anandamide have opposite modulatory actions at the glycine transporter, GLYT1a.
2003,
Pubmed
,
Xenbase
Singh,
Antidepressant binding site in a bacterial homologue of neurotransmitter transporters.
2007,
Pubmed
Singh,
A competitive inhibitor traps LeuT in an open-to-out conformation.
2008,
Pubmed
Succar,
Actions of N-arachidonyl-glycine in a rat inflammatory pain model.
2007,
Pubmed
Supplisson,
Control of NMDA receptor activation by a glycine transporter co-expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Sur,
The therapeutic potential of glycine transporter-1 inhibitors.
2004,
Pubmed
Tonazzi,
Identification by site-directed mutagenesis of a hydrophobic binding site of the mitochondrial carnitine/acylcarnitine carrier involved in the interaction with acyl groups.
2012,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Vandenberg,
Molecular basis for substrate discrimination by glycine transporters.
2007,
Pubmed
,
Xenbase
Vandenberg,
Glycine transport inhibitors as potential antipsychotic drugs.
2001,
Pubmed
Vandenberg,
Serine-O-sulphate transport by the human glutamate transporter, EAAT2.
1998,
Pubmed
,
Xenbase
Vuong,
Actions of N-arachidonyl-glycine in a rat neuropathic pain model.
2008,
Pubmed
Wiles,
N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a.
2006,
Pubmed
,
Xenbase
Xu,
Inhibitors of GlyT1 and GlyT2 differentially modulate inhibitory transmission.
2005,
Pubmed
Yamashita,
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.
2005,
Pubmed
