Among the twenty classical L-amino acids, only glutamate directly activates metabotropic glutamate receptors.
Under pathophysiological conditions, cellular amino acids can be profusely released from cells into the cerebral interstitial space. Because several class-C G protein coupled receptors (GPCRs) display a broad natural ligand spectrum, being sensitive to more than one endogenous ligand, we wondered whether the related metabotropic glutamate (mGlu) receptors could be modulated by various types of L-amino acids, allowing them to sense large increase in extracellular amino acid concentration. Here, the agonist, antagonist and allosteric effects of the twenty classical L-amino acids were evaluated on the eight mGlu receptor subtypes. We show that, in addition to glutamate (Glu), cysteine, aspartate and asparagine also lead to the activation of mGlu3, 4 and 5. Interestingly, our data demonstrate that the effect of these three amino acids did not result from a direct activation of the receptors, but from an indirect action involving Glu-transporters/exchangers. These data first demonstrate that mGlu receptors, unlike other class-C GPCRs, display an extremely high selectivity towards one ligand. Moreover, our results also show that Glu transport systems allow mGlu receptors to sense large increase in the extracellular concentration of some amino acids. Such a system will certainly lead to a large increase in some mGlu receptor activity under pathological conditions, such as seizure, ischemia or other brain injuries.
Frauli
Mélanie
M
Faust Pharmaceuticals SA, Illkirch-Graffenstaden, F-67400, France.
Neuville
Pascal
P
Vol
Claire
C
Pin
Jean-Philippe
JP
Prézeau
Laurent
L
D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D027322:Amino Acid Transport System X-AG; D000596:Amino Acids; D018690:Excitatory Amino Acid Agonists; D050580:Excitatory Amino Acid Transporter 3; D005971:Glutamates; D007295:Inositol Phosphates; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C493400:SLC1A1 protein, human; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D002118:Calcium