Effects of GABA Receptor Antagonists on Retinal Glycine Receptors and on Homomeric Glycine Receptor Alpha Subunits

2005 ◽  
Vol 93 (6) ◽  
pp. 3120-3126 ◽  
Author(s):  
Peiyuan Wang ◽  
Malcolm M. Slaughter
Keyword(s):  
Gaba Receptor ◽  
Ganglion Cells ◽  
Glycine Receptor ◽  
Hek293 Cells ◽  
Receptor Subtypes ◽  
Glycine Receptors ◽  
Receptor Antagonists ◽  
Gaba Antagonists ◽  
Human Embryonic Kidney Cells ◽  
Competitive Inhibitors

Glycinergic and GABAergic inhibition are juxtaposed at one retinal synaptic layer yet likely perform different functions. These functions have usually been evaluated using receptor antagonists. In examining retinal glycine receptors, we were surprised to find that commonly used concentrations of GABA antagonists blocked significant fractions of the glycine current. In retinal amacrine and ganglion cells, the competitive GABAA receptor antagonists (bicuculline and SR95531) were also competitive GlyR antagonists. Picrotoxinin produced a noncompetitive inhibition of retinal GlyRs. [1,2,5,6-tetrahydropyridine-4-yl] methylphosphinic acid, the GABACR antagonist, did not inhibit glycine receptors. All three GABAA receptor antagonists were competitive inhibitors of homomeric α1 or α2 GlyRs expressed in human embryonic kidney cells (HEK293) cells. Interestingly, bicuculline was much more effective at α2 GlyRs and might be used to separate glycine receptor subtypes. Thus commonly used concentrations of GABA antagonists do not unambiguously differentiate GABA and glycine pathways. Picrotoxinin inhibition of GABAC receptors requires two amino acids in the second transmembrane region (TM2): 2′ serine and 6′ threonine. Although TM2 regions in GABA and glycine receptors are highly homologous, neither 2′ serine nor 6′ threonine is essential for picrotoxinin sensitivity in glycine receptors.

Glycine receptor subunit composition alters the action of GABA antagonists

2007 ◽  
Vol 24 (4) ◽  
pp. 513-521 ◽  
Author(s):  
PING LI ◽  
MALCOLM SLAUGHTER
Keyword(s):  
Gaba Receptors ◽  
Gaba Receptor ◽  
Glycine Receptor ◽  
Significant Inhibition ◽  
Hek293 Cells ◽  
Glycine Receptors ◽  
Hek 293 ◽  
293 Cells ◽  
Two Factors ◽  
Α Subunits

GABA receptor antagonists produce an unexpectedly significant inhibition of native glycine receptors in retina and in α1 or α2 homomeric glycine receptors (GlyRs) expressed in HEK 293 cells. In this study we evaluate this phenomenon in heteromeric glycine receptors, formed by mixing α1, α2, and β subunits. Picrotoxinin, picrotin, SR95531, and bicuculline are all more effective antagonists at GlyRs containing α2 subunits than α1 subunits. Inclusion of β subunits reduces the inhibitory potency of picrotoxinin and picrotin but increases the potency of SR95531 and bicuculline. As a result of these two factors, bicuculline is particularly poor at discriminating GABA and glycine receptors. Picrotin, which has been reported to be inactive at GABA receptors, blocks glycine currents in retina and in HEK293 cells, suggesting its utility as a selective glycine antagonist. However, picrotin is a more potent inhibitor of GABA than glycine in retinal neurons. We also tested if GABA and glycine receptor subunits can combine to form functional receptors. If GABAAR γ2S subunits are co-expressed with GlyR α subunits, the mixed receptor is glycine-sensitive and GABA-insensitive. But the mixed receptor exhibits a non-competitive picrotoxinin inhibition that is not observed in the homomeric GlyRs. This suggests that glycine and GABA subunits can co-assemble to form functional glycine receptors.

Glycine receptor immunoreactivity is localized at amacrine synapses in cat retina

1991 ◽  
Vol 7 (6) ◽  
pp. 611-618 ◽  
Author(s):  
Roberta G. Pourcho ◽  
Michael T. Owczarzak
Keyword(s):  
Ganglion Cells ◽  
Glycine Receptor ◽  
Plexiform Layer ◽  
Amacrine Cells ◽  
Bipolar Cells ◽  
Electron Microscopic Level ◽  
Inner Plexiform Layer ◽  
Glycine Receptors ◽  
Electron Microscopic ◽  
Cat Retina

AbstractImmunocytochemical techniques were used to localize strychnine-sensitive glycine receptors in cat retina. Light microscopy showed staining in processes ramifying throughout the inner plexiform layer and in cell bodies of both amacrine and ganglion cells. At the electron-microscopic level, receptor immunoreactivity was seen to be clustered at sites postsynaptic to amacrine cells. In contrast, bipolar cells were neither presynaptic nor postsynaptic elements at sites of glycine receptor staining. Double-label studies verified the presence of glycine immunoreactivity in amacrine terminals presynaptic to glycine receptors. These findings support a role for glycine as an inhibitory neurotransmitter in amacrine cells.

Synaptic connections involving immunoreactive glycine receptors in the turtle retina

1993 ◽  
Vol 10 (5) ◽  
pp. 907-914 ◽  
Author(s):  
Charles L. Zucker ◽  
Berndt Ehinger
Keyword(s):  
Amacrine Cell ◽  
Ganglion Cells ◽  
Glycine Receptor ◽  
Plexiform Layer ◽  
Photoreceptor Cells ◽  
Bimodal Distribution ◽  
Inner Nuclear Layer ◽  
Inner Plexiform Layer ◽  
Glycine Receptors ◽  
Cell Processes

AbstractThe distribution of glycine receptors in the turtle retina was studied with the aid of a monoclonal antibody that detects the 93-kD protein associated with the strychnine-sensitive glycine receptor. Light microscopically, receptors were found in the inner plexiform layer and, more sparsely, in the innermost parts of the inner nuclear layer. No receptors were seen to be associated with photoreceptor cells, horizontal cells, or any other structures in the distal inner nuclear layer or outer plexiform layer. Ultrastructurally, glycine receptors were found on the inner face of postsynaptic membranes of processes from amacrine and presumed ganglion cells and always involved amacrine cell processes as the presynaptic element. Such glycine receptor immunoreactive synapses onto amacrine cell processes were distributed throughout the inner plexiform layer with a peak density near the middle. On the other hand, output synapses onto ganglion cell processes displaying immunoreactive glycine receptor sites showed a bimodal distribution in the inner plexiform layer. Glycine receptor immunoreactivity was not detected on bipolar cells, but presumed glycine-utilizing processes (i.e. those presynaptic to immunoreactive glycine receptors) were occasionally found to be postsynaptic in bipolar cell dyads. The majority of the synaptic input to the presumed glycine-utilizing amacrine cell processes was from other amacrine processes, some of which were themselves glycine utilizing. The observations suggest that glycinergic synapses in the turtle retina are, to a large extent, engaged in processing interamacrine signals.

Expression and distribution of ionotropic glutamate receptor subunits on parasol ganglion cells in the primate retina

2002 ◽  
Vol 19 (4) ◽  
pp. 453-465 ◽  
Author(s):  
BIN LIN ◽  
PAUL R. MARTIN ◽  
ULRIKE GRÜNERT
Keyword(s):  
Glutamate Receptor ◽  
Ganglion Cells ◽  
World Monkey ◽  
Dendritic Tree ◽  
Membrane Properties ◽  
Ionotropic Glutamate Receptor ◽  
Receptor Subtypes ◽  
Glycine Receptors ◽  
Dendritic Field ◽  
Receptor Clusters

The response properties of postreceptoral sensory neurones are determined by the properties of their input neurones, by intrinsic membrane properties, and by the properties of neurotransmitter receptors on the soma and dendritic tree. We previously showed that inhibitory neurotransmitter (GABAA and glycine) receptors on a well-characterised sensory neurone, the parasol ganglion cell in the primate retina, are segregated towards the distal part of the dendritic tree. Here we studied the distribution of excitatory ionotropic glutamate receptor subunits on the dendrites of parasol cells in the retina of a New World monkey, the marmoset, Callithrix jacchus. Individual ganglion cells were intracellularly injected in an in vitro retinal wholemount preparation. Ionotropic glutamate receptor subunits, including AMPA (GluR1-4), kainate (GluR6/7), NMDA (NR1C2′) subunits, and the orphan receptors δ1 and δ2 were visualized with immunocytochemical methods. Immunoreactive puncta that colocalized with the dendrites of ganglion cells were analyzed using standard and/or confocal light microscopy. Colocalized puncta were present on parasol dendrites for all subunits studied, but their density was much lower (approximately 1/5) than previously reported for inhibitory (GABA and glycine) receptors. Segregation of the glutamate receptor clusters (GluR1, GluR6/7 subunits) to the peripheral dendrites was less marked than that shown for GABA and glycine receptor clusters. No sign of segregation of colocalized puncta to the peripheral part of the dendritic field was seen with antibodies to the GluR2, GluR2/3, GluR4, δ1/2, or NR1C2′ subunits. The results suggest that although there is diverse expression of glutamate receptor subtypes, the glutamatergic synapses form only a small proportion of the total synaptic input to primate ganglion cells. They further suggest that the processes which control distribution of excitatory and inhibitory synapses on the dendritic field of ganglion cells are, at least to some extent, independent.

Kavalactones from Kava (Piper methysticum) root extract as modulators of recombinant human glycine receptors

2019 ◽  
Vol 400 (9) ◽  
pp. 1205-1215 ◽  
Author(s):  
Nada Hany Hegazy ◽  
Hans-Georg Breitinger ◽  
Ulrike Breitinger
Keyword(s):  
Glycine Receptor ◽  
Inhibitory Effect ◽  
Hek293 Cells ◽  
Root Extract ◽  
Piper Methysticum ◽  
Dependent Manner ◽  
Glycine Receptors ◽  
Simultaneous Application ◽  
The Individual ◽  
Almost All

Abstract Roots of kava (Piper methysticum) plant are used in almost all Pacific Ocean cultures to prepare a drink with sedative, anesthetic and euphoric properties. One of the main active ingredients of the extract are kava lactones. Here, kava root CO2 extract and three kavalactones, DL-kavain, dihydrokavain and yangonin (isolated from whole extract by column chromatography) were tested for their inhibitory action on recombinant homomeric human α1 glycine receptors expressed in HEK293 cells. Kava CO2 root extract, as well as the individual components DL-kavain, dihydrokavain and yangonin inhibited glycine receptor activity in a dose-dependent manner. DL-kavain was the most potent inhibitor (IC50 = 0.077 ± 0.002 mm), followed by yangonin (IC50 = 0.31 ± 0.04 mm) and dihydrokavain (IC50 = 3.23 ± 0.10 mm) which were 4- and 40-fold less active than DL-kavain, respectively. Application of kava root extract did not reduce maximum currents, but increased EC50 of glycine. Simultaneous application of kava extract and strychnine showed additive inhibition, suggesting that binding of kavalactones and strychnine on the receptor is mutually exclusive. Overall, kavalactones exert a moderate inhibitory effect on the human α1 glycine receptor with DL-kavain being the most potent constituent.

Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

2000 ◽  
Vol 84 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Jiu-Lin Du ◽  
Xiong-Li Yang
Keyword(s):  
Subcellular Localization ◽  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Drug Application ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Receptor Subtypes ◽  
Inner Retina ◽  
Axon Terminals ◽  
Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

Effects of strychnine-insensitive glycine receptor antagonists and sigma agents on working memory performance

1992 ◽  
Vol 3 (4) ◽  
pp. 393???402 ◽  
Author(s):  
D. B. Clissold ◽  
E. W. Karbon ◽  
J. W. Ferkany ◽  
T. Hartman ◽  
M. J. Pontecorvo
Keyword(s):  
Working Memory ◽  
Memory Performance ◽  
Glycine Receptor ◽  
Receptor Antagonists ◽  
Glycine Receptor Antagonists

scholarly journals GLYCINE RECEPTOR ANTIBODY—A MARKER FOR NMO/ NON-MS DEMYELINATION?

2015 ◽  
Vol 86 (11) ◽  
pp. e4.36-e4
Author(s):  
Shahd Hamid ◽  
Liene Elsone ◽  
Patrick Waters ◽  
Mark Woodhall Woodhall ◽  
Kerry Mutch ◽  
...  
Keyword(s):  
Optic Neuritis ◽  
Neurological Disorders ◽  
Glycine Receptor ◽  
Prognostic Significance ◽  
Transverse Myelitis ◽  
Functional Disorders ◽  
Glycine Receptors ◽  
Cns Diseases ◽  
Receptor Antibody

BackgroundAntibodies against glycine receptors (GlyR Ab) have been strongly linked to progressive encephalomyelitis with rigidity and myoclonus (PERM). Their association with other neurological disorders is poorly understood.MethodsWe looked retrospectively at all patients who were tested for (GlyR Abs) in the Walton Centre between 2010–2014.Results138 patients were tested. The pre-test diagnoses (n) were transverse myelitis (34), NMO (22, (7 AQP4 IgG+ve and 15 AQP4 IgG-ve), optic neuritis (17), MS (22), ADEM (4), other atypical demyelination (4), encephalitis (11), epilepsy (4), dementia (4), parkinsonism (3), functional disorders (3) and others (10). 53.6% (74) had a relapsing course6/138 (4%) were positive for GlyR Ab. The diagnoses (n) were optic neuritis (2) one of which was AQP4 IgG+ve, NMO-AQP4-IgG negative (1), transverse myelitis (1), tumefactive demyelination (1) and undiagnosed spastic ataxic syndrome with normal imaging (1). 5/6 had a relapsing course and are on immunosuppressants.ConclusionAntibodies against GlyR are not common and seem to be associated with some non-PERM inflammatory CNS diseases, with a relapsing course. Larger studies are required to understand the clinical and prognostic significance of these early findings.

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