title: The glycine transport inhibitor sarcosine is an inhibitory glycine receptor agonist.
abstract: Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I glycine transporter (GlyT1), an N-methyl-d-aspartate receptor (NMDAR) co-agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and glycine and sarcosine's ability to serve as an NMDAR co-agonist led us to examine whether sarcosine is also an agonist at the inhibitory glycine receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl(-) current that cross-inhibited glycine currents. Sarcosine evoked this current with Li(+) in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR agonist.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hai Xia
authors.initials: HX
authors.lastname: Zhang
authors.forename: Ariel
authors.initials: A
authors.lastname: Lyons-Warren
authors.forename: Liu Lin
authors.initials: LL
authors.lastname: Thio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D018684:Glycine Agents / Q000494:pharmacology; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008094:Lithium / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D018009:Receptors, Glycine / Q000819:agonists*; D012521:Sarcosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013331:Strychnine / Q000494:pharmacology
chemical_list: D002712:Chlorides; D018684:Glycine Agents; D050487:Glycine Plasma Membrane Transport Proteins; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; D018009:Receptors, Glycine; C493267:Slc6a9 protein, mouse; D008094:Lithium; D013331:Strychnine; D005998:Glycine; D012521:Sarcosine