4-METHYLHOMOIBOTENIC ACID ACTIVATES A NOVEL METABOTROPIC GLUTAMATE-RECEPTOR COUPLED TO PHOSPHOINOSITIDE HYDROLYSIS

Metabotropic glutamate receptors (mGluRs) are a family of glutamate re ceptors that are coupled to a variety of second messenger systems thro ugh GTP-binding proteins. Of the eight subtypes cloned to date, mGluR1 and mGluR5 are coupled to phosphoinositide hydrolysis in expression s ystems, and both are activated by the glutamate analogue 1-aminocyclop entane-1S,3R-dicarboxylic acid. Previously, we provided evidence that in rat cortical slices, 4-bromohomoibotenic acid (BrHI) and 4-methylho moibotenic acid (MHI) activate a 1-aminocyclopentane-1S,3R-dicarboxyli c acid-insensitive phosphoinositide hydrolysis-coupled mGluR. We furth er examine these compounds in expression systems. In a stable cell lin e expressing mGluR1a, BrHI is a weak partial agonist whereas MHI has n o agonist activity. In Xenopus oocytes expressing mGluR1a or mGluR5a, BrHI is a weak agonist at mGluRSa whereas MHI is without effect on eit her receptor. Both BrHI and MHI have weak agonist activity at mGluRs 4 a and 7a expressed in stable BHK cell lines whereas neither compound h ad 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 resp onse to DHPG in rat cortical slices. In contrast, LY341495 did not blo ck the phosphoinositide hydrolysis response to MHI in rat cortical sli ces. This provides further evidence that the phosphoinositide hydrolys is response to MHI in rat cortical slices is due to activation of a na vel receptor that is distinct from the previously cloned mGluRs.