Metabotropic Glutamate Receptor Function Research Articles

Evidence for functional metabotropic glutamate receptors in the dorsal cochlear nucleus.

The parallel fibers (PFs) of the dorsal cochlear nucleus (DCN) molecular layer use glutamate as a neurotransmitter. Although metabotropic glutamate receptors (mGluRs) have been identified on cells postsynaptic to the PFs, little is known about the effects of mGluR activation in PF synaptic transmission in the DCN. To investigate these effects, PF-evoked field potentials were recorded from the DCN in guinea pig brain stem slice preparations. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated components of the field response were reversibly depressed by bathing the slice in the mGluR agonists (+/-)-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. A similar depression was produced by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine, but not by the mGluR2/3 agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine or by the mGluR4/6/7/8 agonist L(+)-2-amino-4-phosphonobutyric acid. In addition to the AMPA component, an N-methyl-D-aspartate (NMDA) receptor-dependent component of the field potentials could be identified when the slices were bathed in a low magnesium solution. Under these conditions, the ACPD-induced depression of the AMPA component did not completely recover, whereas the depression of the NMDA component usually recovered and potentiated in some slices. Intracellular recordings of PF-evoked responses were obtained to ascertain which neuronal populations were affected by mGluR activation. Activation of mGluRs produced a reversible depression of PF-evoked responses in cartwheel cells that was not accompanied by any changes in paired-pulse facilitation. The PF-evoked responses recorded from pyramidal cells were unaffected by mGluR activation. Both cell types exhibited a reversible depolarization during (1S,3R)-ACPD application. Subsequent experiments explored the involvement of protein kinases in mediating the effects of mGluRs. The protein kinase C (PKC) activator phorbol-12,13-diacetate partially inhibited the mGluR-mediated depression of the field response; however, the PKC inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide or the protein kinase A inhibitor N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide had little effect on the actions of (1S,3R)-ACPD. These results demonstrate that functional mGluRs are present at PF synapses and are capable of modulating PF synaptic transmission in the DCN.

Functions of metabotropic glutamate receptors in sensory processing in the thalamus

Functions of metabotropic glutamate receptors in sensory processing in the thalamus

A novel metabotropic glutamate receptor agonist: (2 S, 1′ S,2′ R,3′ R)-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine ( cis-MCG-I)

A novel agonist for metabotropic glutamate receptors, (2 S,1′ S,2′ R,3′ R)-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine ( cis-MCG-I), effectively inhibited monosynaptic excitation in newborn rat spinal cords with EC 50 of 3 μM without causing any depolarization. Furthermore, cis-MCG-I inhibited the forskolin-stimulated cyclic AMP formation in rat cultured cortical cells with IC 50 of 1.5 μM. cis-MCG-I neither stimulated the phosphoinositide hydrolysis nor activated ionotropic glutamate receptors even in high concentrations. However, after a brief exposure of spinal cords to quisqualate, it caused depolarization in a dose-dependent manner. This compound would provide useful information for elucidating physiological functions of metabotropic glutamate receptors.

A new metabotropic glutamate receptor agonist: Developmental change of its sensitivity to receptors in the newborn rat spinal cord

A novel metabotropic glutamate receptor agonist, (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), reduced the monosynaptic excitation in newborn rat spinal cord rather than polysynaptic discharges at the nanomolar range without causing postsynaptic depolarization of motoneurones. Its inhibitory action on the monosynaptic excitation reduced in due course of time after birth. On the contrary, the inhibitory action of a metabotropic GABA B receptor agonist, baclofen, did not show marked developmental change. DCG-IV should be expected to have the potential to provide further useful information on the physiological function of metabotropic glutamate receptors.

Presynaptic inhibitory action of a metabotropic glutamate receptor agonist on excitatory transmission in visual cortical neurons.

A family of metabotropic glutamate receptors (mGluRs) has been elucidated by molecular cloning. To study the possible modulatory role of mGluRs in synaptic transmission, we tested the effect of a mGluR agonist, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), on the excitatory post-synaptic currents (EPSCS) recorded from neurons in thin slices of rat visual cortex, by using the whole-cell patch-clamp method. We found that trans-ACPD markedly suppressed the evoked EPSCS without affecting the mean amplitude of spontaneous miniature EPSCS. This effect on the evoked EPSCS was blocked by a potassium channel blocker, 4-aminopyridine (4-AP) in a dose-dependent manner. We suggest that trans-ACPD presynaptically inhibits EPSCS by a mechanism involving the 4-AP-sensitive channels.

Glutamate mediates a slow synaptic response in hippocampal slice cultures

Glutamate (GLU) mediates its 'fast' excitatory transmitter action in the brain by directly gating cation-selective ion channels ('ionotropic' receptors). However, GLU can also activate another type of receptor, coupled to phospholipase C ('metabotropic' receptor). In hippocampal cells, stimulation of this metabotropic receptor by GLU, or by a racemic mixture of (1S-3R and 1R-3S) 1-aminocyclopentyl-1,3-dicarboxylate (ACPD), induces a slower excitation mediated by inhibition of K+ currents. We have assessed whether this slow form of metabotropic receptor excitation can contribute to the effects of synaptically released GLU in hippocampal slice cultures, by recording the responses of CA3 pyramidal cells to afferent mossy fibre stimulation. When the fast ionotropic response was blocked pharmacologically, mossy fibre stimulation produced a slow depolarizing postsynaptic potential associated with a decrease in membrane conductance, a depression of the slow after-hyperpolarization following a train of action potentials, and reduced accommodation during the action potential train. Under voltage-clamp, mossy fibre stimulation produced a slow voltage-dependent inward current which resembled that produced by application of exogenous ACPD or quisqualate (QUIS), and which was occluded by these metabotropic agonists. We therefore suggest that synaptically released GLU can induce two types of postsynaptic responses: a fast excitation through activation of ionotropic receptors and a slower excitation associated with inhibition of K+ conductances through activation of metabotropic receptors. This is analogous to the dual action of acetylcholine on ionotropic (nicotinic) and metabotropic (muscarinic) receptors.

Cardiovascular purinoceptors

Cardiovascular purinoceptors