4-Methylhomoibotenic acid activates a novel metabotropic glutamate receptor coupled to phosphoinositide hydrolysis.

Metabotropic glutamate receptors (mGluRs) are a family of glutamate receptors that are coupled to a variety of second messenger systems through GTP-binding proteins. Of the eight subtypes cloned to date, mGluR1 and mGluR5 are coupled to phosphoinositide hydrolysis in expression systems, and both are activated by the glutamate analogue 1-aminocyclopentane-1S,3R-dicarboxylic acid. Previously, we provided evidence that in rat cortical slices, 4-bromohomoibotenic acid (BrHI) and 4-methylhomoibotenic acid (MHI) activate a 1-aminocyclopentane-1S,3R-dicarboxylic acid-insensitive phosphoinositide hydrolysis-coupled mGluR. We further examine these compounds in expression systems. In a stable cell line expressing mGluR1a, BrHI is a weak partial agonist whereas MHI has no agonist activity. In Xenopus oocytes expressing mGluR1a or mGluR5a, BrHI is a weak agonist at mGluR5a whereas MHI is without effect on either receptor. Both BrHI and MHI have weak agonist activity at mGluRs 4a and 7a expressed in stable BHK cell lines whereas neither compound had any activity on BHK cells expressing mGluR2. Finally, we found that the novel mGluR antagonist LY341495 completely blocked the activation of mGluR1 and mGluR5 and blocked the phosphoinositide hydrolysis response to DHPG in rat cortical slices. In contrast, LY341495 did not block the phosphoinositide hydrolysis response to MHI in rat cortical slices. This provides further evidence that the phosphoinositide hydrolysis response to MHI in rat cortical slices is due to activation of a novel receptor that is distinct from the previously cloned mGluRs.