scholarly journals Distinct mechanisms underlie the subsynaptic mobility of presynaptic metabotropic glutamate receptor types to tune receptor activation

2020 ◽  
Author(s):  
Anna Bodzęta ◽  
Florian Berger ◽  
Harold D. MacGillavry
Keyword(s):  
Synaptic Transmission ◽  
Active Zone ◽  
Metabotropic Glutamate Receptors ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Synaptic Activity ◽  
Control Surface ◽  
Metabotropic Glutamate ◽  
Surface Mobility

ABSTRACTPresynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanisms that control the subsynaptic distribution and mobility of these receptors to contribute to their function are poorly understood. Here, using super-resolution microscopy and single-molecule tracking, we provide novel insights in the molecular mechanisms that control the spatial distribution and mobility of presynaptic mGluRs. We demonstrate that mGluR2 localizes diffusely along the axon and boutons and is highly mobile, while mGluR7 is immobilized specifically at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Indeed, we found that the positioning of mGluR2 is modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone is mediated by its extracellular domain that interacts in trans with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity does not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs determines their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.

Activation of Ca2+-Dependent Currents in Dorsal Root Ganglion Neurons by Metabotropic Glutamate Receptors and Cyclic ADP-Ribose Precursors

1997 ◽  
Vol 77 (5) ◽  
pp. 2573-2584 ◽  
Author(s):  
Jane H. Crawford ◽  
John F. Wootton ◽  
Guy R. Seabrook ◽  
Roderick H. Scott
Keyword(s):  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Dorsal Root Ganglion Neurons ◽  
Metabotropic Glutamate ◽  
Intracellular Ca ◽  
Inward Currents ◽  
Ganglion Neurons

Crawford, Jane H., John F. Wootton, Guy R. Seabrook, and Roderick H. Scott. Activation of Ca2+-dependent currents in dorsal root ganglion neurons by metabotropic glutamate receptors and cyclic ADP-ribose precursors. J. Neurophysiol. 77: 2573–2584, 1997. Cultured dorsal root ganglion neurons were voltage clamped at −90 mV to study the effects of intracellular application of nicotinamide adenine dinucleotide (βNAD+), intracellular flash photolysis of caged 3′,5′-cyclic guanosine monophosphate (cGMP), and metabotropic glutamate receptor activation. The activation of metabotropic glutamate receptors evoked inward Ca2+-dependent currents in most cells. This was mimicked both by intracellular flash photolysis of the caged axial isomer of cGMP [P-1-(2-nitrophenyl)ethyl cGMP] and intracellular application of βNAD+. Whole cell Ca2+-activated inward currents were used as a physiological index of raised intracellular Ca2+ levels. Extracellular application of 10 μM glutamate evoked the activation of Ca2+-dependent inward currents, thus reflecting a rise in intracellular Ca2+ levels. Similar inward currents were also activated after isolation of metabotropic glutamate receptor activation by application of 10 μM glutamate in the presence of 20 μM 6-cyano-7-nitroquinoxaline-2,3-dione and 20 μM dizocilpine maleate (MK 801), or by extracellular application of 10 μM trans-(1 S,3 R)-1-amino-1,3-cyclopentanedicarboxylic acid. Intracellular photorelease of cGMP, from its caged axial isomer, in the presence of βNAD+ was also able to evoke similar Ca2+-dependent inward currents. Intracellular application of βNAD+ alone produced a concentration-dependent effect on inward current activity. Responses to both metabotropic glutamate receptor activation and cGMP were suppressed by intracellular ryanodine, chelation of intracellular Ca2+ by bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid, and depletion of intracellular Ca2+ stores, but were insensitive to the removal of extracellular Ca2+. Therefore both cGMP, possibly via a mechanism that involves βNAD+ and/or cyclic ADP-ribose, and glutamate can mobilize intracellular Ca2+ from ryanodine-sensitive stores in sensory neurons.

Intracellular Ca2+ release mediated by metabotropic glutamate receptor activation in the leech giant glial cell.

1997 ◽  
Vol 200 (19) ◽  
pp. 2565-2573
Author(s):  
C Lohr ◽  
J W Deitmer
Keyword(s):  
Membrane Potential ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Glial Cells ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Cyclopiazonic Acid ◽  
Receptor Activation ◽  
Atpase Inhibitor ◽  
Metabotropic Glutamate

We have investigated the effects of glutamate and glutamate receptor ligands on the intracellular free Ca2+ concentration ([Ca2+]i) and the membrane potential (Em) of single, identified neuropile glial cells in the central nervous system of the leech Hirudo medicinalis. Exposed glial cells of isolated ganglia were filled iontophoretically with the Ca2+ indicator dye Fura-2. Application of glutamate (200-500 mumoll-1) caused biphasic membrane potential shifts and increases in [Ca2+]i, which were only partly reduced by either removing extracellular Ca2+ or blocking ionotropic glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50-100 mumol l-1. Metabotropic glutamate receptor (mGluR) ligands had the following rank of potency in inducing a rise in [Ca2+]i: quisqualate (QQ, 200 mumol l-1) > glutamate (200 mumol l-1) > L(+)2-amino-3-phosphonopropionic acid (L-AP3, 200 mumol l-1 > trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 400 mumol l-1). The mGluR-selective antagonist (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG, 1 mmol l-1] significantly reduced glutamate-evoked increases in [Ca2+]i by 20%. Incubation of the ganglia with the endoplasmic ATPase inhibitor cyclopiazonic acid (CPA, 10 mumol l-1) caused a significant (53%) reduction of glutamate-induced [Ca2+]i transients, while incubation with lithium ions (2 mmol l-1) resulted in a 46% reduction. The effects of depleting the Ca2+ stores with CPA and of CNQX were additive. We conclude that glutamate-induced [Ca2+]i transients were mediated by activation of both Ca(2+)-permeable ionotropic non-NMDA receptors and of metabotropic glutamate receptors leading to Ca2+ release from intracellular Ca2+ stores.

Metabotropic Glutamate Receptor Activation Modulates Sound Level Processing in the Cochlear Nucleus

1998 ◽  
Vol 80 (1) ◽  
pp. 209-217 ◽  
Author(s):  
Dan H. Sanes ◽  
JoAnn McGee ◽  
Edward J. Walsh
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Cochlear Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Sound Level ◽  
Metabotropic Glutamate

Sanes, Dan H., JoAnn McGee, and Edward J. Walsh. Metabotropic glutamate receptor activation modulates sound level processing in the cochlear nucleus. J. Neurophysiol. 80: 209–217, 1998. The principal role of ionotropic glutamate receptors in the transmission and processing of information in the auditory pathway has been investigated extensively. In contrast, little is known about the functional contribution of the G-protein–coupled metabotropic glutamate receptors (mGluRs), although their anatomic location suggests that they exercise a significant influence on auditory processing. To investigate this issue, sound-evoked responses were obtained from single auditory neurons in the cochlear nuclear complex of anesthetized cats and gerbils, and metabotropic ligands were administered locally through microionophoretic pipettes. In general, microionophoresis of the mGluR agonists, (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid or (2 S,1′ S,2′ S)-2-(carboxycyclopropyl)glycine, initially produced a gradual increase in spontaneous and sound-evoked discharge rates. However, activation and recovery times were significantly longer than those observed for ionotropic agonists, such as N-methyl-d-aspartate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, consistent with the recruitment of a second-messenger system. The efficacy of mGluR agonists was diminished after administration of the mGluR antagonist, (+)-α-methyl-4-carboxyphenylglycine, consistent with a selective action at metabotropic recognition sites. In contrast, two distinct changes were observed after the mGluR agonist had been discontinued for several minutes. Approximately 50% of neurons exhibited a chronic depression of sound-evoked discharge rate reminiscent of long-term depression, a cellular property observed in other systems. Approximately 30% of neurons exhibited a long-lasting enhancement of the sound-evoked response similar to the cellular phenomenon of long-term potentiation. These findings suggest that mGluR activation has a profound influence on the gain of primary afferent driven activity in the caudal cochlear nucleus.

Slow Synaptic Inhibition Mediated by Metabotropic Glutamate Receptor Activation of GIRK Channels

2000 ◽  
Vol 84 (5) ◽  
pp. 2284-2290 ◽  
Author(s):  
Patrick Dutar ◽  
Jeffrey J. Petrozzino ◽  
Huan M. Vu ◽  
Marc F. Schmidt ◽  
David J. Perkel
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Brain Slices ◽  
Vocal Learning ◽  
Receptor Activation ◽  
Synaptic Inhibition ◽  
Postsynaptic Inhibition ◽  
Girk Channels ◽  
Metabotropic Glutamate

Glutamate is the predominant excitatory neurotransmitter in the vertebrate CNS. Ionotropic glutamate receptors mediate fast excitatory actions whereas metabotropic glutamate receptors (mGluRs) mediate a variety of slower effects. For example, mGluRs can mediate presynaptic inhibition, postsynaptic excitation, or, more rarely, postsynaptic inhibition. We previously described an unusually slow form of postsynaptic inhibition in one class of projection neuron in the song-control nucleus HVc of the songbird forebrain. These neurons, which participate in a circuit that is essential for vocal learning, exhibit an inhibitory postsynaptic potential (IPSP) that lasts several seconds. Only a portion of this slow IPSP is mediated by GABAB receptors. Since these cells are strongly hyperpolarized by agonists of mGluRs, we used intracellular recording from brain slices to investigate the mechanism of this hyperpolarization and to determine whether mGluRs contribute to the slow synaptic inhibition. We report that mGluRs hyperpolarize these HVc neurons by activating G protein–coupled, inwardly-rectifying potassium (GIRK) channels. MGluR antagonists blocked this response and the slow synaptic inhibition. Thus, glutamate can combine with GABA to mediate slow synaptic inhibition by activating GIRK channels in the CNS.

scholarly journals Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission

2004 ◽  
Vol 1 (4) ◽  
pp. 307-316 ◽  
Author(s):  
QING-SONG LIU ◽  
QIWU XU ◽  
JIAN KANG ◽  
MAIKEN NEDERGAARD
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Group Iii ◽  
Inhibitory Synaptic Transmission ◽  
Metabotropic Glutamate ◽  
Group Ii ◽  
Mglur Antagonist

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca2+ elevation in astrocytes, by photolysis of caged Ca2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca2+-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.

scholarly journals Spatially distinct actions of metabotropic glutamate receptor activation in dorsal lateral geniculate nucleus

2012 ◽  
Vol 107 (4) ◽  
pp. 1157-1163 ◽  
Author(s):  
Gubbi Govindaiah ◽  
Deepa V. Venkitaramani ◽  
Sulalita Chaki ◽  
Charles L. Cox
Keyword(s):  
Lateral Geniculate Nucleus ◽  
Visual Information ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Differential Distribution ◽  
Metabotropic Glutamate ◽  
Lateral Geniculate ◽  
Dorsal Lateral Geniculate

Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN) dynamically communicate visual information from the retina to the neocortex, and this process can be modulated via activation of metabotropic glutamate receptors (mGluRs). Neurons within dLGN express different mGluR subtypes associated with distinct afferent synaptic pathways; however, the physiological function of this organization is unclear. We report that the activation of mGluR5, which are located on presynaptic dendrites of local interneurons, increases GABA output that in turn produces an increased inhibitory activity on proximal but not distal dendrites of dLGN thalamocortical neurons. In contrast, mGluR1 activation produces strong membrane depolarization in thalamocortical neurons regardless of distal or proximal dendritic locations. These findings provide physiological evidence that mGluR1 appear to be distributed along the thalamocortical neuron dendrites, whereas mGluR5-dependent action occurs on the proximal dendrites/soma of thalamocortical neurons. The differential distribution and activation of mGluR subtypes on interneurons and thalamocortical neurons may serve to shape excitatory synaptic integration and thereby regulate information gating through the thalamus.

Group I Metabotropic Glutamate Receptor Activation Produces a Direct Excitation of Identified Septohippocampal Cholinergic Neurons

2004 ◽  
Vol 92 (2) ◽  
pp. 1216-1225 ◽  
Author(s):  
Min Wu ◽  
Tibor Hajszan ◽  
Changqing Xu ◽  
Csaba Leranth ◽  
Meenakshi Alreja
Keyword(s):  
Glutamate Receptor ◽  
Neurodegenerative Disorders ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Cholinergic Neurons ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Double Immunolabeling

Septohippocampal cholinergic neurons innervate the hippocampus and provide it with almost its entire acetylcholine. Axon collaterals of these neurons also release acetylcholine within the septum and thereby maintain the firing activity of septohippocampal GABAergic neurons. A loss of septohippocampal cholinergic neurons occurs in various neurodegenerative disorders associated with cognitive dysfunctions. group I metabotropic glutamate receptors have been implicated in septohippocampal-dependent learning and memory tasks. In the present study, we examined the physiological and pharmacological effects of a potent and selective group I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydroxyphenylglycine (DHPG) on rat septohippocampal cholinergic neurons that were identified in brain slices using a selective fluorescent marker. In whole cell recordings, DHPG produced a reversible, reproducible and a direct postsynaptic and concentration-dependent excitation in 100% of septohippocampal cholinergic neurons tested with an EC50 of 2.1 μM. Pharmacologically, the effects of DHPG were partially/completely reduced by the mGluR1 antagonists, 7-hydrox-iminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester and (+)-2-methyl-4-carboxyphenylglycine. Addition of the mGluR5 antagonist, 2-methyl-6-(phenylethnyl)pyridine hydrochloride, reduced the remaining response to DHPG, suggesting involvement of both receptor subtypes in a subpopulation of septohippocampal cholinergic neurons. In double-immunolabeling studies, 74% of septohippocampal cholinergic neurons co-localized mGluR1α-immunoreactivity and 35% co-localized mGluR5-immunoreactivity. Double-immunolabeling studies at the light and electron-microscopic levels showed that vesicular glutamate transporter 2 terminals make asymmetric synaptic contacts with septohippocampal cholinergic neurons. These findings may be of significance in treatment of cognitive deficits associated with neurodegenerative disorders as a group I mGluR-mediated activation of septohippocampal cholinergic neurons would enhance the release of acetylcholine both in the hippocampus and in the septum.

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