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

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Abstract

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 and mGlu5 receptor responses in Xenopus oocytes. DL-AP3 antagonized mGlu and mGlu5 responses, but antagonism was overcome at high glutamate concentrations consistent with competitive inhibition (IC50 = 2.1 nM for mGlu1α). Both responses were also inhibited by (RS)-α-methyl-4-carboxyphenylglycine (MCPG). We conclude that the available antagonists cannot distinguish between the mGlu 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.

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    Citation Excerpt :

    The ineffectiveness of dl-AP3 suggests that the inhibition of phosphoserine phosphatase (Hawkinson et al., 1996) does not play a role in St I-evoked responses. dl-AP3 is also considered to be a competitive Group I mGlu receptor antagonist (Saugstad et al., 1995). Previous work on St I units found that the broad spectrum competitive mGlu receptor blocker LY341495, at concentrations up to 100 μM sufficient to block all known mGlu receptors, had a weakly excitatory effect (Cahusac and Senok, 2006), an effect which was consistent with the weak excitatory effects of the other antagonists 3-MATIDA, MPEP and MTEP here.

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