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.

Coexpression of Multiple Metabotropic Glutamate Receptors in Axon Terminals of Single Suprachiasmatic Nucleus Neurons

1998 ◽  
Vol 80 (4) ◽  
pp. 1932-1938 ◽  
Author(s):  
Gong Chen ◽  
Anthony N. van den Pol
Keyword(s):  
Glutamate Receptors ◽  
Suprachiasmatic Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Single Neuron ◽  
Gaba Release ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Axon Terminals ◽  
Group I ◽  
Second Messenger Pathways

Chen, Gong and Anthony N. van den Pol. Coexpression of multiple metabotropic glutamate receptors in axon terminals of single suprachiasmatic nucleus neurons. J. Neurophysiol. 80: 1932–1938, 1998. Glutamate is the primary excitatory transmitter in axons innervating the hypothalamic suprachiasmatic nucleus (SCN) and is responsible for light-induced phase shifts of circadian rhythms generated by the SCN. By using self-innervating single neuron cultures and patch-clamp electrophysiology, we studied metabotropic glutamate receptors (mGluRs) expressed by SCN neurons. The selective agonists for group I (3,5-dihydroxy-phenylglycine), group II ((S)-4-carboxy-3-hydroxyphenylglycine), and group III (l(+)-2-amino-4-phosphonobutyric acid) mGluRs all depressed the evoked IPSC in a subset (33%) of single autaptic neurons, suggesting a coexpression of all three groups of mGluRs in the same axon terminals of a single neuron. Other neurons showed a variety of combinations of mGluRs, including an expression of only one group of mGluR (18%) or coexpression of two groups of mGluRs (27%). Some neurons had no response to any of the three agonists (22%). The three mGluR agonists had no effect on postsynaptic γ-aminobutyric acid (GABA) receptor responses, indicating a presynaptic modulation of GABA release by mGluRs. We conclude that multiple mGluRs that act through different second messenger pathways are coexpressed in single axon terminals of SCN neurons where they modulate the release of GABA presynaptically, usually inhibiting release.

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.

Selective Inhibition of Spontaneous But Not Ca2+-Dependent Release Machinery by Presynaptic Group II mGluRs in Rat Cerebellar Slices

2006 ◽  
Vol 96 (1) ◽  
pp. 86-96 ◽  
Author(s):  
Maike Glitsch
Keyword(s):  
Action Potential ◽  
Glutamate Receptors ◽  
Neurotransmitter Release ◽  
Metabotropic Glutamate Receptors ◽  
Gaba Release ◽  
Spontaneous Release ◽  
Metabotropic Receptors ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group Ii

Two main forms of neurotransmitter release are known: action potential-evoked and spontaneous release. Action potential-evoked release depends on Ca2+entry through voltage-gated Ca2+channels, whereas spontaneous release is thought to be Ca2+-independent. Generally, spontaneous and action potential-evoked release are believed to use the same release machinery to release neurotransmitter. This study shows, using the whole cell patch-clamp technique in rat cerebellar slices, that at the interneuron- Purkinje cell synapse activation of presynaptic group II metabotropic glutamate receptors suppresses spontaneous GABA release through a mechanism independent of voltage-gated Ca2+channels, store-operated Ca2+channels, and Ca2+release from intracellular Ca2+stores, suggesting that the metabotropic receptors target the release machinery directly. Voltage gated Ca2+channel-independent release following increased presynaptic cAMP production is similarly inhibited by these metabotropic receptors. In contrast, both voltage-gated Ca2+channel-dependent and presynaptic N-methyl-d-aspartate receptor-dependent GABA release were unaffected by activation of group II metabotropic glutamate receptors. Hence, the mechanisms underlying spontaneous and Ca2+-dependent GABA release are distinct in that only the former is blocked by group II metabotropic glutamate receptors. Thus the same neurotransmitter, glutamate, can activate or inhibit neurotransmitter release by selecting different receptors that target different release machineries.

Groups II and III Metabotropic Glutamate Receptors Differentially Modulate Brief and Prolonged Nociception in Primate STT Cells

2000 ◽  
Vol 84 (6) ◽  
pp. 2998-3009 ◽  
Author(s):  
Volker Neugebauer ◽  
Ping-Sun Chen ◽  
William D. Willis
Keyword(s):  
Glutamate Receptors ◽  
Dorsal Horn ◽  
Central Sensitization ◽  
Metabotropic Glutamate Receptors ◽  
Background Activity ◽  
Mechanical Stimuli ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

The heterogeneous family of G-protein-coupled metabotropic glutamate receptors (mGluRs) provides excitatory and inhibitory controls of synaptic transmission and neuronal excitability in the nervous system. Eight mGluR subtypes have been cloned and are classified in three subgroups. Group I mGluRs can stimulate phosphoinositide hydrolysis and activate protein kinase C whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs share the ability to inhibit cAMP formation. The present study examined the roles of groups II and III mGluRs in the processing of brief nociceptive information and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 11 anesthetized male monkeys ( Macaca fascicularis), extracellular recordings were made from 21 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (brush), marginally and distinctly noxious (press and pinch, respectively) intensity were recorded before, during, and after the infusion of group II and group III mGluR agonists into the dorsal horn by microdialysis. Different concentrations were applied for at least 20 min each (at 5 μl/min) to obtain cumulative concentration-response relationships. Values in this paper refer to the drug concentrations in the microdialysis fibers; actual concentrations in the tissue are about three orders of magnitude lower. The agonists were also applied at 10–25 min after intradermal capsaicin injection. The group II agonists (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (LCCG1, 1 μM-10 mM, n = 6) and (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268; 1 μM-10 mM, n = 6) had no significant effects on the responses to brief cutaneous mechanical stimuli (brush, press, pinch) or on ongoing background activity. In contrast, the group III agonist L(+)-2-amino-4-phosphonobutyric acid (LAP4, 0.1 μM-10 mM, n = 6) inhibited the responses to cutaneous mechanical stimuli in a concentration-dependent manner, having a stronger effect on brush responses than on responses to press and pinch. LAP4 did not change background discharges significantly. Intradermal injections of capsaicin increased ongoing background activity and sensitized the STT cells to cutaneous mechanical stimuli (ongoing activity > brush > press > pinch). When given as posttreatment, the group II agonists LCCG1 (100 μM, n = 5) and LY379268 (100 μM, n = 6) and the group III agonist LAP4 (100 μM, n = 6) reversed the capsaicin-induced sensitization. After washout of the agonists, the central sensitization resumed. Our data suggest that, while activation of both group II and group III mGluRs can reverse capsaicin-induced central sensitization, it is the actions of group II mGluRs in particular that undergo significant functional changes during central sensitization because they modulate responses of sensitized STT cells but have no effect under control conditions.

Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors

2013 ◽  
Vol 74 ◽  
pp. 135-146 ◽  
Author(s):  
David Lodge ◽  
Patrick Tidball ◽  
Marion S. Mercier ◽  
Sarah J. Lucas ◽  
Lydia Hanna ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

scholarly journals Metabotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Francine Acher ◽  
Giuseppe Battaglia ◽  
Hans Bräuner-Osborne ◽  
P. Jeffrey Conn ◽  
Robert Duvoisin ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
G Protein ◽  
Metabotropic Glutamate Receptors ◽  
Transmembrane Domain ◽  
Acid Group ◽  
Allosteric Modulators ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [334]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [190, 262, 255, 386]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [85, 415, 59]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Recent studies revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [86]. Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [422, 257]. The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [29] and antagonized by (S)-hexylhomoibotenic acid [223]. Group-II mGlu receptors may be activated by LY389795 [256], LY379268 [256], eglumegad [337, 416], DCG-IV and (2R,3R)-APDC [338], and antagonised by eGlu [161] and LY307452 [408, 100]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [125]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [176]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

Modulation of mEPSCs in Olfactory Bulb Mitral Cells by Metabotropic Glutamate Receptors

1997 ◽  
Vol 78 (3) ◽  
pp. 1468-1475 ◽  
Author(s):  
N. E. Schoppa ◽  
G. L. Westbrook
Keyword(s):  
Olfactory Bulb ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Mitral Cells ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Selective Agonist ◽  
Group I ◽  
Mepsc Frequency ◽  
Group Ii

Schoppa, N. E. and G. L. Westbrook. Modulation of mEPSCs in olfactory bulb mitral cells by metabotropic glutamate receptors. J. Neurophysiol. 78: 1468–1475, 1997. Olfactory bulb mitral cells express group I (mGluR1), group II (mGluR2), and group III (mGluR7 and mGluR8) metabotropic glutamate receptors. We examined the role of these mGluRs on excitatory synaptic transmission in cultured mitral cells with the use of whole cell patch-clamp recordings. The effects of group-selective mGluR agonists and antagonists were tested on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor-mediated miniature excitatory postsynaptic currents (mEPSCs). (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylate (ACPD) or the group-I-selective agonist 3,5-dihydroxyphenylglycine evoked an inward current accompanied by a decrease in membrane conductance, consistent with the previously described closure of potassium channels by group I agonists. The increased cellular excitability was accompanied by an increase in mEPSC frequency in some cells. When calcium entry was blocked by cadmium, ACPD or the group-II-selective agonist 2-(2,3-dicarboxycyclopropyl)-glycine reduced the mEPSC frequency. l-2-amino-4-phosphonobutyric acid (l-AP4), a group-III-selective agonist, caused a similar decrease. The concentration-dependence ofl-AP4-mediated inhibition was most consistent with activation of mGluR8. We investigated two possible effector mechanisms for the group III presynaptic receptor. Bath application of forskolin or 3-isobutyl-1-methylxantine had no effect on mEPSC frequency. Increasing calcium influx by raising extracellular K+ caused a large increase in the mEPSC frequency but did not enhance l-AP4-mediated inhibition. Thus inhibition of mEPSCs involves a mechanism downstream of calcium entry and appears to be independent of adenosine 3′,5′-cyclic monophosphate. Our results indicate that both group II and III receptors can inhibit glutamate release at mitral cell terminals. Although group II/III receptors had a similar effect on mEPSCs, differences in location on nerve terminals and in glutamate sensitivity suggest that each mGluR may have discrete actions on mitral cell activity.

Sign in / Sign up

Export Citation Format

Share Document