Summary:Purpose: Metabotropic glutamate receptors (mGluRs) might be promising new drug targets for the treatment of epilepsy because the expression of certain mGluRs is regulated in epilepsy and because activation of mGluRs results in distinctive anti-and proconvulsant effects. Therefore, we examined how rnGluR activation modulates high-voltageactivated (HVA) Ca2' channels.Methods: Whole-cell patch-clamp recordings were obtained from granule cells and interneuron-like cells acutely isolated from the dentate gyrus of patients with pharmacoresistent temporal lobe epilepsy.
Results:Agonists selective for either group I or group II mGluRs rapidly and reversibly reduced HVA currents in most dentate gyrus cells. These modulatory effects were inhibited by the respective group I and group IT mGluR antagonists. The specific Ca' " channel antagonists nifedipine and w-conotoxin GVIA potently occluded the effects of group I and II mGluR agonists, respectively, indicating that group I mGluRs acted on L-type channels and group II mGluRs affected N-type channels. About two thirds of the responsive neurons were sensitive either to group I or group II mGluRs, whereas a minority of cells showed effects to agonists of both groups, indicating a variable mGluR expression pattern. Metabotropic (mGluRs) and ionotropic glutamate receptors belong to the family of glutamate receptors. In contrast to the ionotropic receptors, which form ligandgated ion channels, mGluRs influence the activity of membrane enzymes and ion channels by means of G proteins. Thus, mGluRs modulate, rather than mediate, fast synaptic transmission. The mGluRs represent a family of eight subtypes, termed mGluR1 to mGluR8, which are divided into three groups on the basis of sequence homology, transduction pathways, and pharmacologic properties revealed in recombinant expression systems. Group I consists of mGluRl and mGluR5, which are coupled to phosphoinositide hydrolysis. Members of group I1 (mGluR2 and 3) and group LU (mGluR4,