Of the eight cloned metabotropic glutamate receptor (mGluR) subtypes, only group I mGluRs (mGluR1 and 5) have been shown to couple to phosphoinositide (PI) hydrolysis. Both group I mGluRs are activated by 1S,3R-ACPD. Previously, we provided evidence that 4-bromohomoibotenic acid (BrHI) and 4-methylhomoibotenic acid (MHI) activate a 1S,3R-ACPD-insensitive PI hydrolysis-coupled mGluR in rat cortical slices. We now show that concentrations of MHI that elicit a maximal PI hydrolysis response in rat cortical slices are ineffective at activation of either mGluR1 or mGluR5 in expression systems. BrHI, on the other hand, is a weak partial agonist at both mGluRs 1 and 5. BrHI and MHI are ineffective at the group II mGluR, mGluR2, and have only slight effects on group III mGluRs (mGluR4 and 7). In addition, in Xenopus oocytes expressing mGluR1 or 5, the response to MHI and 1S,3R-ACPD are not additive, indicating that synergism of the compounds on existing receptors cannot account for the additivity of the PI hydrolysis response in cortical slices. We have now begun to determine the electrophysiological effects of MHI. In the presence of NBQX, MHI elicits a rapidly desensitizing inward current in cultured cortical neurons which is not mimicked by DHPG, DCG-IV, or L-AP4, suggesting that MHI is not eliciting this effect through activation of known mGluRs, but possibly through a novel PI hydrolysis-linked mGluR. Funded by NIH grants NS-31373 and MH-10940.