L-2-amino-3-phosphonopropionic acid competitively antagonizes metabotropic glutamate receptors 1α and 5 in Xenopus oocytes

The aspartate analog 2-amino-3-phosphonopropionic acid (AP3) antagonizes glutamate-stimulated phosphatidyl inositide hydrolysis in brain slices, but is reportedly weak or ineffective in antagonizing the phosphatidyl inositide-coupled cloned metabotropic glutamate receptors 1α and 5. Thus we examined the pharmacological properties of AP3 on mGlu_1α and mGlu₅ receptor responses in Xenopus oocytes. DL-AP3 antagonized mGlu_1α and mGlu₅ responses, but antagonism was overcome at high glutamate concentrations consistent with competitive inhibition (IC₅₀ = 2.1 nM for mGlu_1α). Both responses were also inhibited by (RS)-α-methyl-4-carboxyphenylglycine (MCPG). We conclude that the available antagonists cannot distinguish between the mGlu_1α receptor and mGlu₅ receptor, and that antagonism by AP3 may be obscured in the presence of high agonist concentrations or in cells with spare receptors.