Group I Metabotropic Glutamate Receptors Mediate Slow Inhibition of Calcium Current in Neocortical Neurons

1998 ◽  
Vol 80 (4) ◽  
pp. 1981-1988 ◽  
Author(s):  
Rod J. Sayer
Keyword(s):  
Charge Carrier ◽  
Glutamate Receptors ◽  
Calcium Current ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Direct Action ◽  
Metabotropic Glutamate ◽  
Neocortical Neurons ◽  
Group I

Sayer, Rod J. Group I metabotropic glutamate receptors mediate slow inhibition of calcium current in neocortical neurons J. Neurophysiol. 80: 1981–1988, 1998. Metabotropic glutamate receptor (mGluR)-mediated inhibition of high-voltage-activated Ca2+ currents was investigated in pyramidal neurons acutely isolated from rat dorsal frontoparietal neocortex. Whole cell recordings were made at 30–32°C, with Ca2+ as the charge carrier. Selective agonists were used to classify the subgroup of mGluRs mediating the response. Ca2+ currents were inhibited by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and by the group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) but not by the group II agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) or the group III agonist l(+)-2-amino-4-phosphonobutryic acid (l-AP4). (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (l-CCG-I) was effective at 10 and 100 μM but not at 1 μM, consistent with involvement of group I mGluRs. Variable results were obtained with the putative mGluR5-selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the putative mGluR1-selective antagonist (S)-4-carboxyphenylglycine [(S)-4CPG], indicating that the group I mGluR subtypes may vary between cells or that these compounds were activating other receptors. The actions of (+)-α-methyl-4-carboxyphenylglycine [(+)-MCPG] were consistent with it being a low-potency antagonist. Several features of the Ca2+ current inhibition evoked by DHPG distinguished it from the rapid modulation typical of a direct action of G proteins on Ca2+ channels; the inhibition was slow to reach maximum (tens of seconds), current activation was not slowed or shifted in the positive voltage direction, and the inhibition was not relieved by positive prepulses. Nimodipine and ω-conotoxin GVIA blocked fractions of the current and also reduced the magnitude of the responses to DHPG, indicating that both L- and N-type Ca2+ channels were regulated. These results further differentiate the slow modulatory pathway observed in neocortical neurons when Ca2+ is used as the charge carrier from the rapid voltage-dependent mechanism reported to inhibit Ba2+ currents under Ca2+-free conditions.

Modulation of Multiple Potassium Currents by Metabotropic Glutamate Receptors in Neurons of the Hypothalamic Supraoptic Nucleus

1997 ◽  
Vol 78 (6) ◽  
pp. 3428-3437 ◽  
Author(s):  
L. A. Schrader ◽  
J. G. Tasker
Keyword(s):  
Glutamate Receptors ◽  
Supraoptic Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Outward Current ◽  
Magnocellular Neurons ◽  
Inward Current ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group I

Schrader, L. A. and J. G. Tasker. Modulation of multiple potassium currents by metabotropic glutamate receptors in neurons of the hypothalamic supraoptic nucleus. J. Neurophysiol. 78: 3428–3437, 1997. We studied the effects of activation of the metabotropic glutamate receptors on intrinsic currents of magnocellular neurons of the supraoptic nucleus (SON) with whole cell patch-clamp and conventional intracellular recordings in coronal slices (400 μm) of the rat hypothalamus. Trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid ( trans-ACPD, 10–100 μM), a broad-spectrum metabotropic glutamate receptor agonist, evoked an inward current (18.7 ± 3.45 pA) or a slow depolarization (7.35 ± 4.73 mV) and a 10–30% decrease in whole cell conductance in ∼50% of the magnocellular neurons recorded at resting membrane potential. The decrease in conductance and the inward current were caused largely by the attenuation of a resting potassium conductance because they were reduced by the replacement of intracellular potassium with an equimolar concentration of cesium or by the addition of potassium channel blockers to the extracellular medium. In some cells, trans-ACPD still elicited a small inward current after blockade of potassium currents, which was abolished by the calcium channel blocker, CdCl2. Trans-ACPD also reduced voltage-gated and Ca2+-activated K+ currents in these cells. Trans-ACPD reduced the transient outward current ( I A) by 20–70% and/or the I A-mediated delay to spike generation in ∼60% of magnocellular neurons tested. The cells that showed a reduction of I A generally also showed a 20–60% reduction in a voltage-gated, sustained outward current. Finally, trans-ACPD attenuated the Ca2+-dependent outward current responsible for the afterhyperpolarization ( I AHP) in ∼60% of cells tested. This often revealed an underlying inward current thought to be responsible for the depolarizing afterpotential seen in some magnocellular neurons. (RS)-3,5-dihydroxyphenylglycine, a group I receptor-selective agonist, mimicked the effects of trans-ACPD on the resting and voltage-gated K+ currents. (RS)-α-methyl-4-carboxyphenylglycine, a group I/II metabotropic glutamate receptor antagonist, blocked these effects. A group II receptor agonist, 2S,1′S,2′S-2carboxycyclopropylglycine and a group III receptor agonist, l(+)-2-amino-4-phosphonobutyric acid, had no effect on the resting or voltage-gated K+ currents, indicating that the reduction of K+ currents was mediated by group I receptors. About 80% of the SON cells that were labeled immunohistochemically for vasopressin responded to metabotropic glutamate receptor activation, whereas only 33% of labeled oxytocin cells responded, suggesting that metabotropic receptors are expressed preferentially in vasopressinergic neurons. These data indicate that activation of the group I metabotropic glutamate receptors leads to an increase in the postsynaptic excitability of magnocellular neurons by blocking resting K+ currents as well as by reducing voltage-gated and Ca2+-activated K+ currents.

Activation of Metabotropic Glutamate Receptors Modulates the Voltage-Gated Sustained Calcium Current in a Teleost Horizontal Cell

1999 ◽  
Vol 81 (2) ◽  
pp. 425-434 ◽  
Author(s):  
Cindy L. Linn ◽  
Adele C. Gafka
Keyword(s):  
Glutamate Receptors ◽  
Calcium Current ◽  
Metabotropic Glutamate Receptors ◽  
Horizontal Cell ◽  
Horizontal Cells ◽  
Group Iii ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

Activation of metabotropic glutamate receptors modulates the voltage-gated sustained calcium current in a teleost horizontal cell. In the teleost retina, cone horizontal cells contain a voltage-activated sustained calcium current, which has been proposed to be involved in visual processing. Recently, several studies have demonstrated that modulation of voltage-gated channels can occur through activation of metabotropic glutamate receptors (mGluRs). Because glutamate is the excitatory neurotransmitter in the vertebrate retina, we have used whole cell electrophysiological techniques to examine the effect of mGluR activation on the sustained voltage-gated calcium current found in isolated cone horizontal cells in the catfish retina. In pharmacological conditions that blocked voltage-gated sodium and potassium channels, as well as N-methyl-d-aspartate (NMDA) and non-NMDA channels, application of l-glutamate or 1-aminocyclopentane-1,3-dicarboxylic acid (1 S,3 R-ACPD) to voltage-clamped cone horizontal cells acted to increase the amplitude of the calcium current, expand the activation range of the calcium current by 10 mV into the cell’s physiological operating range, and shift the peak calcium current by −5 mV. To identify and characterize the mGluR subtypes found on catfish cone horizontal cells, agonists of group I, group II, or group III mGluRs were applied via perfusion. Group I and group III mGluR agonists mimicked the effect of l-glutamate or 1 S,3 R-ACPD, whereas group II mGluR agonists had no effect on L-type calcium current activity. Inhibition studies demonstrated that group I mGluR antagonists significantly blocked the modulatory effect of the group I mGluR agonist, ( S)-3,5-dihydroxyphenylglycine. Similar results were obtained when the group III mGluR agonist,l-2-amino-4-phosphonobutyric acid, was applied in the presence of a group III mGluR antagonist. These results provide evidence for two groups of mGluR subtypes on catfish cone horizontal cells. Activation of these mGluRs is linked to modulation of the voltage-gated sustained calcium current.

A Novel Binding Assay For Metabotropic Glutamate Receptors Using [3H] ʟ-Quisqualic Acid And Recombinant Receptors

2002 ◽  
Vol 57 (3-4) ◽  
pp. 348-355 ◽  
Author(s):  
Hiroshi Ohashi ◽  
Takaharu Maruyama ◽  
Hidemi Higashi-Matsumoto ◽  
Takashi Nomoto ◽  
Yutaka Takeuchi
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Radioligand Binding ◽  
Receptor Expression ◽  
Metabotropic Glutamate ◽  
Quisqualic Acid ◽  
Recombinant Receptors ◽  
Group I ◽  
Recombinant Type

We established a methodology to analyze radioligand binding to the recombinant type 1a metabotropic glutamate receptor (mGluR1a). A full-length ᴄDNA encoding mGluR1a, which was isolated from a λ gt 11 ᴄDNA library of human cerebellar origin, was expressed in a baculovirus/Sf9 insect cell system. Membrane fractions with recombinant receptor expression were analyzed for the binding of [3H]L-quisqualic acid (ʟ-QA), which is known to be a potent agonist of mGluR1a. Efficient binding of the radioligand to the human receptor was observed in a saturable manner, giving an apparent Kd= 0.091 μᴍ. [3H]ʟ-QA bound to the human mGluR1a was displaced by known ligands such as ʟ-QA, ʟ-Glu, t-ACPD(( ±)-1- aminocyclopentane-trans-1,3-dicarboxylic acid) with IC50s = 0.056, 0.97 and 4.0 μᴍ, respectively. MCPG (α-methyl-4-carboxyphenylglycine) displaced the radioligand binding with lower potency. Using this binding protocol, we then evaluated the ligand ability of synthetic dipeptides. Among peptides tested, only Glu-containing dipeptides inhibited the radioligand binding, e.g. IC50 of ʟ-Met-ʟ-Glu was 4.3 μᴍ. When phosphatidyl inositol turnover was assayed in mGluR1a-expressing CHO cells, ʟ-Met-ʟ-Glu was partially agonistic. We further expanded this [3H]ʟ-QA binding protocol to type 5a mGluR, another member of group I mGluRs, as well as to AMPA receptor, a member of ionotropic glutamate receptors, since ʟ-QA is also known to be a potent ligand for these receptors. Data shown here will provide a novel system not only to search for ligands for the glutamate receptors, but also to biochemically analyze the interaction modes between glutamate receptors and their ligands

β-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons

2005 ◽  
Vol 93 (6) ◽  
pp. 3102-3111 ◽  
Author(s):  
Joanna P. Tyszkiewicz ◽  
Zhen Yan
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptors ◽  
Cortical Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Amyloid Peptide ◽  
Metabotropic Glutamate ◽  
Prefrontal Cortical ◽  
Group I ◽  
Β Amyloid

The metabotropic glutamate receptors (mGluRs) have been implicated in cognition, memory, and some neurodegenerative disorders, including the Alzheimer's disease (AD). To understand how the dysfunction of mGluRs contributes to the pathophysiology of AD, we examined the β-amyloid peptide (Aβ)-induced alterations in the physiological functions of mGluRs in prefrontal cortical pyramidal neurons. Two potential targets of mGluR signaling involved in cognition, the GABAergic system and the N-methyl-d-aspartate (NMDA) receptor, were examined. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) amplitude, and this effect was protein kinase C (PKC) sensitive. Treatment with Aβ abolished the DHPG-induced enhancement of sIPSC amplitude. On the other hand, activation of group II mGluRs with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly increased the NMDA receptor (NMDAR)-mediated currents via a PKC-dependent mechanism, and Aβ treatment also diminished the APDC-induced potentiation of NMDAR currents. In Aβ-treated slices, both DHPG and APDC failed to activate PKC. These results indicate that the mGluR regulation of GABA transmission and NMDAR currents is impaired by Aβ treatment probably due to the Aβ-mediated interference of mGluR activation of PKC. This study provides a framework within which the role of mGluRs in normal cognitive functions and AD can be better understood.

scholarly journals Excitation of Cerebellar Interneurons by Group I Metabotropic Glutamate Receptors

2004 ◽  
Vol 92 (3) ◽  
pp. 1558-1565 ◽  
Author(s):  
Movses H. Karakossian ◽  
Thomas S. Otis
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Ampa Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Low Frequency ◽  
Parallel Fiber ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Group I

Cerebellar basket and stellate neurons (BSNs) provide feed-forward inhibition to Purkinje neurons (PNs) and thereby play a principal role in determining the output of the cerebellar cortex. During low-frequency transmission, glutamate released at parallel fiber synapses excites BSNs by binding to AMPA receptors; high-frequency transmission also recruits N-methyl-d-aspartate (NMDA) receptors. We find that, in addition to these ligand-gated receptors, a G-protein–coupled glutamate receptor subtype participates in exciting BSNs. Stimulation of metabotropic glutamate receptor 1α (mGluR1α) with the mGluR agonist ( RS)-3,5-dihydroxyphenylglycine (DHPG) leads to an increase in spontaneous firing of BSNs and indirectly to an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in PNs. Under conditions in which ligand-gated glutamate receptors are blocked, parallel fiber stimulation generates a slow excitatory postsynaptic current (EPSC) in BSNs that is inhibited by mGluR1α-selective antagonists. This slow EPSC is capable of increasing BSN spiking and indirectly increasing sIPSCs frequency in PNs. Our findings reinforce the idea that distinct subtypes of glutamate receptors are activated in response to different patterns of activity at excitatory synapses. The results also raise the possibility that mGluR1α-dependent forms of synaptic plasticity may occur at excitatory inputs to BSNs.

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