Modulation of Calcium Channels by Group I and Group II Metabotropic Glutamate Receptors in Dentate Gyrus Neurons from Patients with Temporal Lobe Epilepsy

Abstract

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,

mGluR1 enhances efferent inhibition of inner hair cells in the developing rat cochlea

“…In the developing cochlea, P/Q-type and N-type Ca 2+ channels support efferent release of neurotransmitter, whereas L-type Ca 2+ channels suppress release by activating Ca 2+ -dependent large conductance potassium (BK) channels that repolarize the efferent terminals (Zorrilla de San Martin et al 2010). Previous work in central neurons has shown that agonists of mGluRs can reduce currents through L-type Ca 2+ channels (Sayer et al 1992;Sahara & Westbrook, 1993;Pin & Duvoisin, 1995;Schumacher et al 2000). Thus, group I mGluR activation in the developing cochlea might enhance efferent inhibition by suppressing L-type Ca 2+ channels, preventing activation of BK channels, and prolonging terminal depolarization and neurotransmitter release.…”

“…; Sahara & Westbrook, ; Pin & Duvoisin, ; Schumacher et al . ). Thus, group I mGluR activation in the developing cochlea might enhance efferent inhibition by suppressing L‐type Ca 2+ channels, preventing activation of BK channels, and prolonging terminal depolarization and neurotransmitter release.…”

Repeated Cocaine Administration Attenuates Group I Metabotropic Glutamate Receptor-Mediated Glutamate Release and Behavioral Activation: A Potential Role for Homer

“…The involvement of action potentials in the elevation of extracellular glutamate by DHPG could indicate that the effect is not mediated by presynaptic terminals. However, the capacity of mGluR1 and mGluR5 to increase cytosolic Ca 2ϩ via stimulating release from the endoplasmic reticulum or opening L-type Ca 2ϩ channels indicates a presynaptic priming effect on vesicular release that would not necessarily be revealed by blocking action potential-induced activation of N-type Ca 2ϩ channels (Kammermeier et al, 2000;Schumacher et al, 2000). Demonstrating a priming action by mGluR1 and mGluR5, Cochilla and Alford (1998) found that although mGluR1 stimulation did not produce excitatory potentials, it potentiated the magnitude of electrically stimulated EPSPs in motor neurons.…”

Group II Metabotropic Glutamate Receptors Modulate Extracellular Glutamate in the Nucleus Accumbens

“…Group II mGluRs have been previously shown to be G icoupled, negative modulators of L-and N-type Ca 2ϩ channels in electrophysiological studies using brain slices, neuronal cultures, and heterologous expression systems (Chivas et al, 1994;Schumacher et al, 2000). Similarly, in vitro and in vivo release studies reveal L-and N-type channel involvement in the inhibition of dopamine release by group II mGluRs (Hu et al, 1999).…”