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.

Group I Metabotropic Glutamate Receptors Mediate an Inward Current in Rat Substantia Nigra Dopamine Neurons That Is Independent From Calcium Mobilization

1999 ◽  
Vol 82 (4) ◽  
pp. 1974-1981 ◽  
Author(s):  
Ezia Guatteo ◽  
Nicola B. Mercuri ◽  
Giorgio Bernardi ◽  
Thomas Knöpfel
Keyword(s):  
Substantia Nigra ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Inward Current ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Rat Substantia Nigra

Metabotropic glutamate receptors modulate neuronal excitability via a multitude of mechanisms, and they have been implicated in the pathogenesis of neurodegenerative processes. Here we investigated the responses mediated by group I metabotropic glutamate receptors (mGluRs) in dopamine neurons of the rat substantia nigra pars compacta, using whole cell patch-clamp recordings in combination with microfluorometric measurements of [Ca2+]i and [Na+]i. The selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) was bath-applied (20 μM, 30 s to 2 min) or applied locally by means of short-lasting (2–4 s) pressure pulses, delivered through an agonist-containing pipette positioned close to the cell body of the neuron. 3,5-DHPG evoked an inward current characterized by a transient and a sustained component, the latter of which was uncovered only with long-lasting agonist applications. The fast component coincided with a transient elevation of [Ca2+]i, whereas the total current was associated with a rise in [Na+]i. These responses were not affected either by the superfusion of ionotropic excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and d-2-amino-5-phosphono-pentanoic acid (d-APV), nor by the sodium channel blocker tetrodotoxin (TTX). (S)-α-methyl-4-carboxyphenylglycine (S-MCPG) and the more selective mGluR1 antagonist 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate (CPCCOEt) depressed both 3,5-DHPG–induced inward current components and, although less effectively, the associated [Ca2+]i elevations. On repeated agonist applications the inward current and the calcium transients both desensitized. The time constant of recovery from desensitization differed significantly between these two responses, being 67.4 ± 4.4 s for the inward current and 28.6 ± 2.7 s for the calcium response. Bathing the tissue in a calcium-free/EGTA medium or adding thapsigargin (1 μM) to the extracellular medium prevented the generation of the [Ca2+]i transient, but did not prevent the activation of the inward current. These electrophysiological and fluorometric results show that the 3,5-DHPG–induced inward current and the [Ca2+]i elevations are mediated by independent pathways downstream the activation of mGluR1.

Presynaptic Modulation by Metabotropic Glutamate Receptors of Excitatory and Inhibitory Synaptic Inputs to Hypothalamic Magnocellular Neurons

1997 ◽  
Vol 77 (2) ◽  
pp. 527-527 ◽  
Author(s):  
L. A. Schrader ◽  
J. G. Tasker
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Gaba Release ◽  
Metabotropic Receptors ◽  
Presynaptic Terminals ◽  
Magnocellular Neurons ◽  
Group Iii ◽  
Synaptic Inputs ◽  
Metabotropic Glutamate ◽  
Group I

Schrader, L. A. and J. G. Tasker. Presynaptic modulation by metabotropic glutamate receptors of excitatory and inhibitory synaptic inputs to hypothalamic magnocellular neurons. J. Neurophysiol. 77: 527–536, 1997. The effects of activation of metabotropic glutamate receptors (mGluRs) on synaptic inputs to magnocellular neurons of the hypothalamic supraoptic nucleus (SON) were studied with the use of whole cell patch-clamp and microelectrode recordings in acute hypothalamic slices. Application of the mGluR agonist trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid ( trans-ACPD, 100 μM) elicited an increase in the frequency of spontaneous excitatory postsynaptic potentials (EPSPs) and excitatory postsynaptic currents (EPSCs) in 20% of the cells, and of spontaneous inhibitory postsynaptic potentials (IPSPs) and inhibitory postsynaptic currents (IPSCs) in 50% of the cells tested in normal medium. The increased frequency of spontaneous EPSPs/EPSCs and IPSPs/IPSCs was blocked by tetrodotoxin (TTX), indicating that mGluRs act to excite the somata/dendrites of presynaptic glutamatergic and GABAergic neurons. (RS)-3,5-dihydroxyphenylglycine (50 μM), a selective group I receptor agonist, mimicked the presynaptic somatic/dendritic effects of trans-ACPD, suggesting that the presynaptic somatic/dendritic receptors responsible for increased spike-dependent glutamate and γ-aminobutyric acid (GABA) release belong to the group I mGluRs. In the presence of TTX, trans-ACPD caused a decrease in the frequency of miniature EPSCs (up to 90%) in 13 of 16 cells, and a decrease in the frequency of miniature IPSCs (up to 80%) in 10 of 16 cells tested. Miniature EPSC and IPSC amplitudes usually did not change in trans-ACPD, suggesting that activation of metabotropic receptors located at presynaptic glutamatergic and GABAergic terminals led to a reduction in transmitter release onto SON magnocellular neurons. l(+)-2-amino-4-phosphonobutyric acid (100–250 μM), a selective group III receptor agonist, mimicked the effects of trans-ACPD at presynaptic terminals, decreasing the frequency of miniature EPSCs and IPSCs by up to 85% without affecting their amplitude. Thus the metabotropic receptors at presynaptic glutamate and GABA terminals in the SON belong to group III mGluRs. EPSCs evoked by electrical stimulation were enhanced by the group III receptor antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid, suggesting that presynaptic metabotropic receptors are activated by the release of endogenous glutamate. These data indicate that mGluRs in the hypothalamus have opposing actions at presynaptic somata/dendrites and at presynaptic terminals. Activation of group I receptors (mGluR1 and/or mGluR5) on presynaptic somata/dendrites led to an increase in spike-dependent transmitter release, whereas activation of the group III receptors (mGluR4, 7, and/or 8) on presynaptic terminals suppressed glutamate and GABA release onto SON neurons. No diffferences were seen in the effects of mGluR activation between immunohistochemically identified oxytocin and vasopressin neurons of the SON.

Metabotropic Glutamate Receptor Enhancement of Spontaneous IPSCs in Neocortical Interneurons

1997 ◽  
Vol 78 (5) ◽  
pp. 2287-2295 ◽  
Author(s):  
Fu-Ming Zhou ◽  
John J. Hablitz
Keyword(s):  
Glutamate Receptor ◽  
Time Constant ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Slow Component ◽  
Voltage Range ◽  
Inward Current ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Layer I

Zhou, Fu-Ming and John J. Hablitz. Metabotropic glutamate receptor enhancement of spontaneous IPSCs in neocortical interneurons. J. Neurophysiol. 78: 2287–2295, 1997. Using neocortical layer I neurons as a model for GABAergic interneurons, we have studied γ-aminobutyric acid-A (GABAA) receptor-mediated spontaneous inhibitory postsynaptic currents (IPSCs) and modulation by metabotropic glutamate receptors (mGluRs). In the presence of 0.5 μM tetrodotoxin (TTX) and ionotropic glutamate receptor antagonists and under symmetrical Cl− conditions, the mean amplitude of miniature IPSCs (mIPSCs) was ∼50 pA at a holding potential of −70 mV with individual events ranging from 10 to 400 pA. Averaged mIPSCs had a 10–90% rise time of ∼0.6 ms. The decay was double exponential. The fast component had a time constant of ∼4 ms and comprised ∼40% of the total amplitude. The slow component had a time constant of ∼22 ms. The frequency of spontaneous IPSCs (sIPSCs), recorded in the absence of TTX, was increased by bath application of the mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 10–100 μM) or the group I mGluR selective agonist quisqualic acid (Quis; 0.5–1 μM). Under identical conditions, mIPSCs were not affected. The kinetics of sIPSCs and mIPSCs were not altered by ACPD or Quis. Quis (1 μM) induced an inward current of ∼70 pA at a holding potential of −70 mV, whereas ACPD (40–200 μM) induced a smaller inward current. This current was linear over the voltage range −70 to +30 mV and reversed polarity near 0 mV. In current-clamp recordings, both Quis and ACPD induced a depolarization and action potential firing in layer I and deeper layer interneurons. We conclude that neocortical layer I neurons receive GABAA receptor-mediated inhibitory synaptic inputs. Activation of mGluRs, possibly mGluR1 and/or mGluR5, causes an enhancement of inhibitory synaptic transmission by directly depolarizing corticalGABAergic interneurons through the opening of nonselective cation channels.

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.

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

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.

scholarly journals Activation of Metabotropic Glutamate Receptors Inhibits High-Voltage-Gated Calcium Channel Currents of Chicken Nucleus Magnocellularis Neurons

2005 ◽  
Vol 93 (3) ◽  
pp. 1418-1428 ◽  
Author(s):  
Yong Lu ◽  
Edwin W Rubel
Keyword(s):  
High Voltage ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Inhibitory Effect ◽  
Nucleus Magnocellularis ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Highly Active ◽  
Group I ◽  
Channel Currents

Using whole cell patch-clamp recordings, we pharmacologically characterized the voltage-gated Ca2+ channel (VGCC) currents of chicken nucleus magnocellularis (NM) neurons using barium as the charge carrier. NM neurons possessed both low- and high-voltage-activated Ca2+ channel currents (HVA IBa2+). The N-type channel blocker (ω-conotoxin-GVIA) inhibited more than half of the total HVA IBa2+, whereas blockers of L- and P/Q-type channels each inhibited a small fraction of the current. Metabotropic glutamate receptor (mGluR)-mediated modulation of the HVA IBa2+ was examined by bath application of glutamate (100 μM), which inhibited the HVA IBa2+ by an average of 16%. The inhibitory effect was dose dependent and was partially blocked by ω-conotoxin-GVIA, indicating that mGluRs modulate N and other type HVA IBa2+. The nonspecific mGluR agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarbosylic acid (1S,3R-ACPD), mimicked the inhibitory effect of glutamate on HVA IBa2+. Group I–III mGluR agonists showed inhibition of the HVA current with the most potent being the group III agonist l(+)-2-amino-4-phosphonobutyric acid. 1S,3R-ACPD (200 μM) had no effect on K+ or Na+ currents. The firing properties of NM neurons were also not altered by 1S,3R-ACPD. We propose that the inhibition of VGCC currents by mGluRs limits depolarization-induced Ca2+ entry into these highly active NM neurons and regulates their Ca2+ homeostasis.

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