Heterogeneous expression of GABA receptor‐like subunits LCCH3 and GRD reveals functional diversity of GABA receptors in the honeybee
            
              Apis mellifera

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

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Pathway-Specific Targeting of GABAA Receptor Subtypes to Somatic and Dendritic Synapses in the Central Amygdala

Journal of Neurophysiology ◽

10.1152/jn.2001.86.2.717 ◽

2001 ◽

Vol 86 (2) ◽

pp. 717-723 ◽

Cited By ~ 41

Author(s):

Andrew J. Delaney ◽

Pankaj Sah

Keyword(s):

Gaba Receptors ◽

Large Amplitude ◽

Gaba Receptor ◽

Small Amplitude ◽

Inhibitory Synapses ◽

Receptor Subtypes ◽

Central Amygdala ◽

Low Concentrations ◽

Gabaa Receptor Subtypes ◽

Minimal Stimulation

Neurons in the central amygdala express two distinct types of ionotropic GABA receptor. One is the classical GABAA receptor that is blocked by low concentrations of bicuculline and positively modulated by benzodiazepines. The other is a novel type of ionotropic GABA receptor that is less sensitive to bicuculline but blocked by the GABAC receptor antagonist (1,2,5,6-tetrohydropyridine-4-yl) methylphosphinic acid (TPMPA) and by benzodiazepines. In this study, we examine the distribution of these two receptor types. Recordings of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) showed a wide variation in amplitude. Most events had amplitudes of <50 pA, but a small minority had amplitudes >100 pA. Large-amplitude events also had rise times faster than small-amplitude events. Large-amplitude events were fully blocked by 10 μM bicuculline but unaffected by TPMPA. Small amplitude events were partially blocked by both bicuculline and TPMPA. Focal application of hypertonic sucrose to the soma evoked large-amplitude mIPSCs, whereas focal dendritic application of sucrose evoked small-amplitude mIPSCs. Thus inhibitory synapses on the dendrites of neurons in the central amygdala express both types of GABA receptor, but somatic synapses expressed purely GABAA receptors. Minimal stimulation revealed that inhibitory inputs arising from the laterally located intercalated cells innervate dendritic synapses, whereas inhibitory inputs of medial origin innervated somatic inhibitory synapses. These results show that different types of ionotropic GABA receptors are targeted to spatially and functionally distinct synapses. Thus benzodiazepines will have different modulatory effects on different inhibitory pathways in the central amygdala.

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Homomeric RDL and Heteromeric RDL/LCCH3 GABA Receptors in the Honeybee Antennal Lobes: Two Candidates for Inhibitory Transmission in Olfactory Processing

Journal of Neurophysiology ◽

10.1152/jn.00798.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 458-468 ◽

Cited By ~ 31

Author(s):

Julien Pierre Dupuis ◽

Michaël Bazelot ◽

Guillaume Stéphane Barbara ◽

Sandrine Paute ◽

Monique Gauthier ◽

...

Keyword(s):

Information Processing ◽

Chloride Channel ◽

Gaba Receptors ◽

Gaba Receptor ◽

Chloride Channels ◽

Physiological Role ◽

Inhibitory Transmission ◽

Olfactory Information ◽

Whole Cell Patch Clamp ◽

Inward Currents

γ-Aminobutyric acid (GABA)–gated chloride channel receptors are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing. In an effort to understand the nature and properties of the ionotropic receptors involved in these processes in the honeybee Apis mellifera, we performed a pharmacological and molecular characterization of GABA-gated channels in the primary olfactory neuropile of the honeybee brain—the antennal lobe (AL)—using whole cell patch-clamp recordings coupled with single-cell RT-PCR. Application of GABA onto AL cells at −110 mV elicited fast inward currents, demonstrating the existence of ionotropic GABA-gated chloride channels. Molecular analysis of the GABA-responding cells revealed that both subunits RDL and LCCH3 were expressed out of the three orthologs of Drosophila melanogaster GABA-receptor subunits encoded within the honeybee genome (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila ; LCCH3, ligand-gated chloride channel homologue 3), opening the door to possible homo- and/or heteromeric associations. The resulting receptors were activated by insect GABA-receptor agonists muscimol and CACA and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline, displaying a typical RDL-like pharmacology. Interestingly, increasing the intracellular calcium concentration potentiated GABA-elicited currents, suggesting a modulating effect of calcium on GABA receptors possibly through phosphorylation processes that remain to be determined. These results indicate that adult honeybee AL cells express typical RDL-like GABA receptors whose properties support a major role in synaptic inhibitory transmission during olfactory information processing.

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GABA receptors on the cell-body membrane of an identified insect motor neuron

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1988.0006 ◽

1988 ◽

Vol 232 (1269) ◽

pp. 443-456 ◽

Cited By ~ 46

Keyword(s):

Motor Neuron ◽

Cell Body ◽

Chloride Channel ◽

Gaba Receptors ◽

Gaba Receptor ◽

Periplaneta Americana ◽

Rank Order ◽

Chloride Ions ◽

Resting Membrane Potential ◽

Induced Current

The pharmacology of a γ-aminobutyric acid (GABA) receptor on the cell body of an identified motor neuron of the cockroach ( Periplaneta americana ) was investigated by current-clamp and voltage-clamp methods. Iontophoretic application of GABA increased membrane conductance to chloride ions, and prolonged application resulted in desensitization. Hill coefficients, determined from dose–response data, indicated that binding of at least two GABA molecules was required to activate the chloride channel. Differences between vertebrate GABA A receptors and insect neuronal GABA receptors were detected. For the GABA receptor of motor neuron D f , the following rank order of potency was observed: isoguvacine > muscimol ≽ GABA > 3-aminopropanesulphonic acid. The GABA B receptor agonist baclofen was inactive. Of the potent vertebrate GABA receptor antagonists (bicuculline, pitrazepin, RU5135 and picrotoxin), only picrotoxin (10 –7 M) produced a potent, reversible block of the response to GABA of motor neuron D f . Both picrotoxinin and picrotin also blocked GABA-induced currents. Bicuculline hydrochloride (10 –4 M) and bicuculline methiodide (10 –4 M) were both ineffective when applied at resting membrane potential (–65 mV), although at hyper-polarized levels partial block of GABA-induced current was sometimes observed. Pitrazepin (10 –4 M) caused a partial, voltage-independent block of GABA-induced current. The steroid derivative RU5135 was inactive at 10 –5 M. In contrast to the potent competitive blockade of vertebrate GABA A receptors by bicuculline, pitrazepin and RU5135, none of the weak antagonism caused by these drugs on the insect GABA receptor was competitive. Flunitrazepam (10 –6 M) potentiated GABA responses, providing evidence for a benzodiazepine site on an insect GABA-receptor–chloride-channel complex.

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Intracortical Pathway Involving Dysgranular Cortex Conveys Hindlimb Inputs to S-I Forelimb-Stump Representation of Neonatally Amputated Rats

Journal of Neurophysiology ◽

10.1152/jn.2001.85.1.407 ◽

2001 ◽

Vol 85 (1) ◽

pp. 407-413 ◽

Cited By ~ 8

Author(s):

Andrey S. Stojic ◽

Richard D. Lane ◽

Robert W. Rhoades

Keyword(s):

Somatosensory Cortex ◽

Recent Work ◽

Gaba Receptors ◽

Gaba Receptor ◽

Cobalt Chloride ◽

Primary Somatosensory Cortex ◽

Receptor Blockade ◽

Neuronal Circuit ◽

Treatment Results

Reorganization of the primary somatosensory cortex (S-I) forelimb-stump representation of rats that sustained neonatal forelimb removal is characterized by the expression of hindlimb inputs that are revealed when cortical GABA receptors are pharmacologically blocked. Recent work has shown that the majority of these inputs are transmitted from the S-I hindlimb representation to the forelimb-stump field via an, as yet, unidentified pathway between these regions. In this study, we tested the possibility that hindlimb inputs to the S-I forelimb-stump representation of neonatally amputated rats are conveyed through an intracortical pathway between the S-I hindlimb and forelimb-stump representations that involves the intervening dysgranular cortex by transiently inactivating this area and evaluating the effect on hindlimb expression in the S-I forelimb-stump representation during GABA receptor blockade. Of 332 S-I forelimb-stump recording sites from six neonatally amputated rats, 68.3% expressed hindlimb inputs during GABA receptor blockade. Inactivation of dysgranular cortex with cobalt chloride (CoCl2) resulted in a significant decrease in the number of hindlimb responsive sites (9.5%, P < 0.001 vs. cortex during GABA receptor blockade before CoCl2 treatment). Results were also compiled from S-I forelimb recording sites from three normal rats: 14.1% of 136 sites were responsive to the hindlimb during GABA receptor blockade, and all of these responses were abolished during inactivation of dysgranular cortex with CoCl2 ( P < 0.05). These results indicate that the S-I hindlimb representation transmits inputs to the forelimb-stump field of neonatally amputated rats through a polysynaptic intracortical pathway involving dysgranular cortex. Furthermore the findings from normal rats suggest that this pathway might reflect the amplification of a neuronal circuit normally present between the two representations.

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Kinetic parameters of GABA receptor binding by rat adenohypophysis membranes under conditions of modeling various levels of corticosteroids and ACGT in the body

Problems of Endocrinology ◽

10.14341/probl11949 ◽

1993 ◽

Vol 39 (6) ◽

pp. 43-46

Author(s):

T. M. Mishunina ◽

V. Ya. Kononenko

Keyword(s):

Kinetic Parameters ◽

Gaba Receptors ◽

Gaba Receptor ◽

Plasma Membranes ◽

Specific Binding ◽

The Body ◽

Noticeable Increase ◽

High Affinity ◽

Gaba Binding ◽

Hormonal Levels

Kinetic parameters of l4C-GABA specific binding by rat adenohypophyseal plasma membranes were studied in experiments on modelling various corticosteroid and ACTH levels in animal body. A single hydrocortisone injection did not change Ka for high- and low-affinity GABA receptors, the number of the former (Bmax) increasing in this case. Repeated hydrocortisone injections were associated with Ko reduction for high-affinity GABA receptors and a noticeable increase of Kn for low-affinity receptors, with their number reducing. ACTH injection did not change the kinetic parameters of GABA binding with receptors. The number of high-affinity GABA receptors and their affinity reduced after removal of adrenals whereas the number of low-affinity receptors in this case was increasing. A single hydrocortisone injection to adrenalectomized rats had a normalizing effect on adenohypophyseal GABA receptors. Analysis of the results and changes in blood hormonal levels indicated that affinity changes in high-affinity receptors and changed number of low-affinity adenohypophyseal GABA receptors correlated with changes in ACTH and hydrocortisone changes.

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Effects of the arylaminopyridazine-GABA derivatives, sr95103 and SR95531 on the Ascaris muscle GABA receptor: the relative potency of the antagonists in Ascaris is different to that at vertebrate GABA, receptors

Comparative Biochemistry and Physiology Part C Comparative Pharmacology ◽

10.1016/0742-8413(91)90227-k ◽

1991 ◽

Vol 98 (2-3) ◽

pp. 417-422 ◽

Cited By ~ 4

Author(s):

A.H. Duittoz ◽

R.J. Martin

Keyword(s):

Gaba Receptors ◽

Gaba Receptor ◽

Relative Potency ◽

Gaba Derivatives

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Respiratory depression produced by activation of GABA receptors in hindbrain of cat

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.5.1278 ◽

1981 ◽

Vol 51 (5) ◽

pp. 1278-1286 ◽

Cited By ~ 46

Author(s):

K. A. Yamada ◽

P. Hamosh ◽

R. A. Gillis

Keyword(s):

Tidal Volume ◽

Respiratory Rate ◽

Respiratory Depression ◽

Gaba Receptors ◽

Gaba Receptor ◽

Respiratory Activity ◽

Aminobutyric Acid ◽

Neural Pathways ◽

Gamma Aminobutyric Acid ◽

Respiratory Responses

Respiratory responses to activation of gamma-aminobutyric acid (GABA) receptors in the hindbrain were measured in chloralose-anesthetized cats using a Fleisch pneumotachograph. GABA receptors were activated by intracisternal injections of muscimol and GABA. Muscimol (0.05--6.65 micrograms) administered to seven animals caused a depression of respiratory activity with apnea occurring in each animal. Before apnea occurred, a decrease in tidal volume was observed (from 25.7 +/- 0.9 to 14.7 +/- 1.1 ml). Respiratory rate and inspiratory and expiratory durations were unchanged. GABA (0.05--12.15 mg) administered to five animals produced the same effect as muscimol on respiratory activity. Apnea produced by both agents was reversed by intracisternal administration of the GABA-receptor antagonist drug, bicuculline. Administration of bicuculline to four naive animals increased tidal volume (from 31.3 +/- 1.7 to 36.5 +/- 0.7 ml) but had no effect on either respiratory rate or inspiratory duration. These results indicate that activation of GABA receptors causes respiratory depression and suggest that GABA may be an important neurotransmitter in CNS neural pathways involved in regulating respiratory activity.

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Effect of GABA on basal and vagally mediated gastric acid secretion and hormone release in dogs

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1988.254.5.g723 ◽

1988 ◽

Vol 254 (5) ◽

pp. G723-G731

Author(s):

R. C. Thirlby ◽

M. H. Stevens ◽

A. J. Blair ◽

F. Petty ◽

I. L. Crawford ◽

...

Keyword(s):

Acid Secretion ◽

Gastric Acid Secretion ◽

Gastric Acid ◽

Blood Brain Barrier ◽

Gaba Receptors ◽

Gaba Receptor ◽

Receptor Agonist ◽

Acid Output ◽

Gastric Fistula ◽

Heidenhain Pouch

To stimulate peripheral gamma-aminobutyric acid (GABA) receptors, GABA, which does not cross the blood-brain barrier, was administered to dogs with vagally innervated gastric fistulas at intravenous doses of 0, 0.66, 2, 6, 18, and 54 micrograms.kg-1.min-1. Mean gastric acid output increased from zero basally to 3.0 +/- 1.4 mmol/h during infusion of 54 micrograms.kg-1.min-1 GABA. Plasma somatostatin-like immunoreactivity decreased significantly below basal levels during infusion of 54 micrograms.kg-1.min-1 GABA (P less than 0.05). To stimulate central nervous system GABA receptors as well as peripheral GABA receptors, progabide, a GABA-receptor agonist, which readily crosses the blood-brain barrier, was injected intravenously. Mean acid output was 3.5 +/- 1.3 mmol/h after 20 mg/kg progabide and 0.6 +/- 0.5 mmol/h after its vehicle (P less than 0.05). Basal serum gastrin concentration increased significantly after progabide injection. Acid output during insulin-induced hypoglycemia was inhibited 59% by 30 mg/kg intravenous progabide. Progabide infusion also diminished or abolished circulating gastrin, somatostatin, and pancreatic polypeptide responses during insulin-induced hypoglycemia (P less than 0.05). Further studies were performed in dogs with a gastric fistula and a vagally denervated Heidenhain pouch to confirm that GABA-receptor stimulation affects acid secretion via peripheral pathways. Intravenous injection of baclofen (0.5 mg/kg), a GABAB-receptor agonist, increased acid secretion significantly from the gastric fistula and the Heidenhain pouch. These studies suggest that GABA may play a role in regulating gastric acid secretion and gastrointestinal and pancreatic endocrine function by both central and peripheral mechanisms.

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Two Metabotropic γ-Aminobutyric Acid Receptors Differentially Modulate Calcium Currents in Retinal Ganglion Cells

The Journal of General Physiology ◽

10.1085/jgp.110.1.45 ◽

1997 ◽

Vol 110 (1) ◽

pp. 45-58 ◽

Cited By ~ 43

Author(s):

Jian Zhang ◽

Wen Shen ◽

Malcolm M. Slaughter

Keyword(s):

Retinal Ganglion Cells ◽

Gaba Receptors ◽

Gaba Receptor ◽

Ganglion Cells ◽

Calcium Currents ◽

Gabab Receptors ◽

Aminobutyric Acid ◽

Retinal Ganglion ◽

Wide Range ◽

Prepulse Facilitation

Metabotropic γ-aminobutyric acid (GABA) receptors were studied in amphibian retinal ganglion cells using whole cell current and voltage clamp techniques. The aim was to identify the types of receptor present and their mechanisms of action and modulation. Previous results indicated that ganglion cells possess two ionotropic GABA receptors: GABAAR and GABACR. This study demonstrates that they also possess two types of metabotropic GABAB receptor: one sensitive to baclofen and another to cis-aminocrotonic acid (CACA). The effects of these selective agonists were blocked by GDP-β-S. Baclofen suppressed an ω-conotoxin–GVIA-sensitive barium current, and this action was reversed by prepulse facilitation, indicative of a direct G-protein pathway. The effect of baclofen was also partially occluded by agents that influence the protein kinase A (PKA) pathway. But the effect of PKA activation was unaffected by prepulse facilitation, indicating PKA acted through a parallel pathway. Calmodulin antagonists reduced the action of baclofen, whereas inhibitors of calmodulin phosphatase enhanced it. Antagonists of internal calcium release, such as heparin and ruthenium red, did not affect the baclofen response. Thus, the baclofen-sensitive receptor may respond to influx of calcium. The CACA-sensitive GABA receptor reduced current through dihydropyridine-sensitive channels. Sodium nitroprusside and 8-bromo-cGMP enhanced the action of CACA, indicating that a nitric oxide system can up-regulate this receptor pathway. CACA-sensitive and baclofen-sensitive GABAB receptors reduced spike activity in ganglion cells. Overall, retinal ganglion cells possess four types of GABA receptor, two ionotropic and two metabotropic. Each has a unique electrogenic profile, providing a wide range of neural integration at the final stage of retinal information processing.

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