Fast Potentiation of Glycine Receptor Channels by Intracellular Calcium in Neurons and Transfected Cells

Fucile, Sergio; Jan, Didier De Saint; Carvalho, Lia Prado de; Bregestovski, Pìotr

doi:10.1016/s0896-6273(00)00134-3

Cited by 67 publications

(85 citation statements)

References 56 publications

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“…However, these data are not in good agreement with previous studies that reported that splicing of the long insert into GlyR ␣3 mRNA impacts on desensitization kinetics (12, 39 -41). Notably, desensitization of GlyR channels may be highly variable (20,41) and influenced by many parameters, such as receptor density (42), membrane potential (43), intracellular and extracellular pH (44,45), ion concentration (46,47), the membrane lipid composition, and phosphorylation of the intracellular TM3-TM4 domain or the N-glycosylation of the receptor N terminus (20). Technical features, such as slow or fast ligand application or the ligand concentration (16,48), duration of ligand administration, or the recording mode may also account for these differences.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Raltschev

Hetsch

Winkelmann

et al. 2016

Journal of Biological Chemistry

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Glycine receptors are chloride-permeable, ligand-gated ion channels and contribute to the inhibition of neuronal firing in the central nervous system or to facilitation of neurotransmitter release if expressed at presynaptic sites. Recent structure-function studies have provided detailed insights into the mechanisms of channel gating, desensitization, and ion permeation. However, most of the work has focused only on comparing a few isoforms, and among studies, different cellular expression systems were used. Here, we performed a series of experiments using recombinantly expressed homomeric and heteromeric glycine receptor channels, including their splice variants, in the same cellular expression system to investigate and compare their electrophysiological properties. Our data show that the current-voltage relationships of homomeric channels formed by the ␣2 or ␣3 subunits change upon receptor desensitization from a linear to an inwardly rectifying shape, in contrast to their heteromeric counterparts. The results demonstrate that inward rectification depends on a single amino acid (Ala 254 ) at the inner pore mouth of the channels and is closely linked to chloride permeation. We also show that the current-voltage relationships of glycine-evoked currents in primary hippocampal neurons are inwardly rectifying upon desensitization. Thus, the alanine residue Ala 254 determines voltage-dependent rectification upon receptor desensitization and reveals a physio-molecular signature of homomeric glycine receptor channels, which provides unprecedented opportunities for the identification of these channels at the single cell level.

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Section: Discussionmentioning

confidence: 99%

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Raltschev

Hetsch

Winkelmann

et al. 2016

Journal of Biological Chemistry

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“…However, it is interesting that the changes we observed in receptor expression coincide with changes in Ca 2ϩ channel expression in the calyx (28), just preceding the maturation of hearing. Enhancement of average intraterminal Ca 2ϩ levels might trigger down-regulation of GABA A receptor (29) and enhancement of glycine receptor activity (30,31). Molecular and biophysical analysis of GABA A receptor expression during development will be required to clarify this issue.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal developmental regulation of presynaptic ionotropic receptors

Tureček

Trussell

2002

Proc. Natl. Acad. Sci. U.S.A.

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Activation of ionotropic glycine receptors potentiates glutamate release in mature calyceal nerve terminals of the rat medial nucleus of the trapezoid body, an auditory brainstem nucleus. In young rats, glycine and its receptors are poorly expressed. We therefore asked whether GABA (␥-aminobutyric acid) might play a larger role than glycine in the regulation of glutamate release in the absence of glycine receptors. Indeed, in rats younger than postnatal day 11 (P11), and before the onset of hearing, calyces expressed high levels of ionotropic GABAA receptors but few glycine receptors. Isoguvacine, a selective agonist at GABAA receptors, strongly enhanced excitatory postsynaptic currents in young rats but had little effect in rats older than P11. Down-regulation of presynaptic GABAA receptors did not reflect global changes in receptor expression, because the magnitude of GABA and glycine responses was similar at P13 in the parent-cell bodies of the calyces, the bushy cells of the cochlear nucleus. In outside-out patches excised from the nonsynaptic face of calyces, GABA and glycine evoked singlechannel currents consistent with the properties of postsynaptic GABAA and glycine receptors. Inhibitory GABAB receptors were present on the calyx at all developmental stages examined. Thus, GABA initially acts on two receptor subtypes, both promoting and inhibiting glutamate release. With age, the former role is transferred to the glycine receptor during the period in which postsynaptic glycinergic transmission is acquired. L igand-gated ion channels (ionotropic receptors) aggregate in subsynaptic membrane shortly after pre-and postsynaptic cells come in close contact (1-4). During maturation of the synapse, changes often occur in the subtypes of postsynaptic receptor (5, 6). Recently, it has become clear that many synapses contain presynaptic ionotropic receptors, such as glutamate, GABA A (␥-aminobutyric acid type A), or acetylcholine receptors, whose activation regulates transmitter release in response to presynaptic action potentials (7). Unlike many postsynaptic receptors, it is not known whether presynaptic receptors are expressed in parallel with the development of their corresponding transmitter systems. This problem is accentuated by the fact that presynaptic receptors generally are not directly apposed to presynaptic terminals (axo-axonic synapses) but, rather, are activated by ''spillover'' of transmitter from distant terminals (8, 9). Moreover, it is not known whether these receptors are selectively targeted to axon terminals or, instead, appear in proportion to global changes in receptor expression over the entire neuron.The calyx of Held is a large glutamatergic nerve terminal found on neurons of the medial nucleus of the trapezoid body (MNTB), a brainstem auditory relay nucleus. Postsynaptic neurons in MNTB are glycinergic and supply fast inhibition to diverse targets in the superior olivary complex. We previously have shown that presynaptic glycine receptors are expressed on the calyx terminal and that acti...

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“…S3A) Signaling Events Underlying IL-1β-Mediated GlyR LTP. Postsynaptic Ca 2+ can increase glycine receptor-mediated currents, both by modulating open channel probability (11) and by increasing the dwell time of glycine receptors at synapses (10). We therefore tested whether intracellular Ca 2+ is necessary for GlyR LTP by chelating intracellular Ca 2+ in the postsynaptic GABAergic lamina II cell.…”

Section: Il-1β Potentiates Glycinergic Synapses On Lamina II Gabaergicmentioning

confidence: 99%

“…GlyR LTP may require Ca 2+ -mediated glycine receptor delivery to synapses, as chelating postsynaptic Ca 2+ was sufficient to impair LTP induction. Alternatively, IL-1β may increase channel open probability rather than number; glycinergic currents and single-channel openings are transiently increased by Ca 2+ (11), or by a number of neuromodulators downstream of intracellular Ca 2+ , including PKC, calcium/calmodulin-dependent protein kinase II, and endocannabinoids (11,(54)(55)(56)(57)(58)(59)(60)(61)(62). Similar signaling processes may mediate LTP described at goldfish Mauthner cell glycinergic synapses, where underlying mechanisms have not been investigated (63).…”

Section: Glycine Receptor Trafficking and Channel Properties Modulatementioning

confidence: 99%

“…Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8,9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.…”

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confidence: 99%

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Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

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Fast Potentiation of Glycine Receptor Channels by Intracellular Calcium in Neurons and Transfected Cells

Cited by 67 publications

References 56 publications

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Reciprocal developmental regulation of presynaptic ionotropic receptors

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

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