Functional and Pharmacological Aspects of GABA Transporters

2007 ◽  
pp. 285-303 ◽  
Author(s):  
K. Madsen ◽  
H. S. White ◽  
R. P. Clausen ◽  
B. Frølund ◽  
O. M. Larsson ◽  
...  
Keyword(s):  
Gaba Transporters

scholarly journals The Dual Role of the GABAA Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats

2021 ◽  
Vol 22 (13) ◽  
pp. 6772
Author(s):  
Michele Malaguarnera ◽  
Tiziano Balzano ◽  
Mari Carmen Castro ◽  
Marta Llansola ◽  
Vicente Felipo
Keyword(s):  
Gabaa Receptors ◽  
Motor Impairment ◽  
Minimal Hepatic Encephalopathy ◽  
Peripheral Inflammation ◽  
Membrane Expression ◽  
Gabaergic Neurotransmission ◽  
Gaba Transporters ◽  
Suitable Target ◽  
Gabaa Antagonist

Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABAA receptors can modulate cerebellar neuroinflammation. The GABAA antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABAA receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABAA receptors could be a suitable target for improving neuroinflammation in MHE.

scholarly journals 4-Aminobutyrate (GABA) transporters from the amine-polyamine-choline superfamily: substrate specificity and ligand recognition profile of the 4-aminobutyrate permease from Bacillus subtilis

1998 ◽  
Vol 333 (3) ◽  
pp. 565-571 ◽  
Author(s):  
Casey E. BRECHTEL ◽  
Steven C. KING
Keyword(s):  
Bacillus Subtilis ◽  
Culture Conditions ◽  
Ligand Recognition ◽  
Open Chain ◽  
Conformationally Constrained ◽  
E Coli ◽  
Gaba Transporters ◽  
Transport Defect ◽  
Gaba Analogues ◽  
Limited Culture

A previous study [Ferson, Wray and Fisher (1996) Mol. Microbiol. 22, 693–701] has shown that transposon-mediated disruption of a protein 47% identical to the Escherichia coli GABA (4-aminobutyrate) transporter abolishes the ability of nitrogen-limited culture conditions to induce expression of a GABA transport activity in Bacillus subtilis. Here it is demonstrated directly that the B. subtilis GABA permease (gabP) gene can complement the transport defect in the gabP-negative E. colistrain. Unexpectedly, the ligand-recognition profile of the B. subtilis GabP was found to differ substantially from that of the highly homologous E. coli GabP. Unlike the E. coli GabP, the B. subtilis GabP: (i) exhibits approx. equal preference for the 3-carbon (β-alanine, Km = 9.6 µM) and the 4-carbon (GABA, Km = 37 µM) amino acids, and (ii) resists inhibition by bulky, conformationally constrained compounds (e.g. nipecotic acid, guvacine), which are active against GABA transporters from brain. The present study shows additionally that the B. subtilis GabP can translocate several open-chain GABA analogues (3-aminobutyrate, 3-aminopropanoate, cis-4-aminobutenoate) across the membrane via counterflow against [3H]GABA. Thus, consistent with the idea that the ligand-recognition domain of the B. subtilis GabP is less spacious than that of the close homologue from E. coli, the former exhibits more stringent requirements than the latter for substrate recognition and translocation. These distinct functional characteristics of the E. coli and B. subtilis GABA transporters provide a basis by which to identify ligand-recognition domains within the amine-polyamine-choline transporter superfamily.

Structure, function and brain localization of neurotransmitter transporters.

1994 ◽  
Vol 196 (1) ◽  
pp. 283-295 ◽  
Author(s):  
F Jursky ◽  
S Tamura ◽  
A Tamura ◽  
S Mandiyan ◽  
H Nelson ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Specific Binding ◽  
Site Directed Mutagenesis ◽  
Binding Studies ◽  
Inhibitory System ◽  
Cytochemical Localization ◽  
Gaba Transporters ◽  
Glycine Transporter ◽  
Neurotransmitter Transporters ◽  
Glycine Transporters

We studied four different cDNAs encoding GABA transporters and three different cDNAs encoding glycine transporters in mouse and rat brains. A genomic clone of two of the glycine transporters (GLYT1a and GLYT1b) revealed that they derive from differential splicing of a single gene. The third glycine transporter (GLYT2) is encoded by a separate gene. Antibodies were raised against seven of these neurotransmitter transporters and their cytochemical localization in the mouse brain was studied. In general, we observed a deviation from the classical separation of neuronal and glial transporters. It seems that each of the neurotransmitter transporters is present in specific places in the brain and is expressed in a different way in very specific areas. For example, the GABA transporter GAT4, which also transports beta-alanine, was localized to neurons. However, GAT1, which is specific for GABA, was localized not only to neurons but also to glial cells. The recently discovered glycine transporter GLYT2 was of particular interest because of its deviation from the general structure by a very extended N terminus containing multiple potential phosphorylation sites. Western analysis and immunocytochemistry in frozen sections of mouse brain demonstrated a clear caudal-rostral gradient of GLYT2 distribution, with massive accumulation in the spinal cord and brainstem and less in the cerebellum. Its distribution is typically neuronal and it is present in processes with varicosities. A correlation as observed between the pattern we obtained and that observed previously from strychnine binding studies. The results indicate that GLYT2 is involved in the termination of glycine neurotransmission at the classical inhibitory system in the hindbrain. The availability of four different GABA transporters made it possible to look for specific binding sites upon the neurotransmitter transporters. An extensive program of site-directed mutagenesis led us to identify a potential neurotransmitter binding site on the GABA transporters.

Astrocytic GABA Transporters: Pharmacological Properties and Targets for Antiepileptic Drugs

2017 ◽  
pp. 283-296 ◽  
Author(s):  
Arne Schousboe ◽  
Petrine Wellendorph ◽  
Bente Frølund ◽  
Rasmus P. Clausen ◽  
Povl Krogsgaard-Larsen
Keyword(s):  
Antiepileptic Drugs ◽  
Pharmacological Properties ◽  
Gaba Transporters

GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus

2003 ◽  
Vol 90 (4) ◽  
pp. 2690-2701 ◽  
Author(s):  
Kimmo Jensen ◽  
Chi-Sung Chiu ◽  
Irina Sokolova ◽  
Henry A. Lester ◽  
Istvan Mody
Keyword(s):  
Gaba Release ◽  
Gabab Receptors ◽  
Acid Decarboxylase ◽  
Wild Type ◽  
Gaba Transporter ◽  
Inhibitory Neurotransmitter ◽  
Gaba Transporters ◽  
Gaba Transporter 1 ◽  
Glutamic Acid Decarboxylase 65 ◽  
Deficient Mice

After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.

scholarly journals GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons

2017 ◽  
Vol 118 (6) ◽  
pp. 3092-3106 ◽  
Author(s):  
Michael Moldavan ◽  
Olga Cravetchi ◽  
Charles N. Allen
Keyword(s):  
Circadian Clock ◽  
Suprachiasmatic Nucleus ◽  
Dependent Manner ◽  
Circadian Period ◽  
Gaba Concentration ◽  
Gaba Transporter ◽  
Concentration Dependent Manner ◽  
Gaba Transport ◽  
Gaba Transporters ◽  
Tonic Current

GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN. NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

scholarly journals Functional remodeling of subtype-specific markers surrounding implanted neuroprostheses

2017 ◽  
Vol 118 (1) ◽  
pp. 194-202 ◽  
Author(s):  
Joseph W. Salatino ◽  
Bailey M. Winter ◽  
Matthew H. Drazin ◽  
Erin K. Purcell
Keyword(s):  
Motor Cortex ◽  
Glutamate Transporter ◽  
Microelectrode Arrays ◽  
Morphological Characteristics ◽  
Neuronal Loss ◽  
Adult Rats ◽  
Gaba Transporters ◽  
Synaptic Markers ◽  
Transporter Expression ◽  
Observation Period

Microelectrode arrays implanted in the brain are increasingly used for the research and treatment of intractable neurological disease. However, local neuronal loss and glial encapsulation are known to interfere with effective integration and communication between implanted devices and brain tissue, where these observations are typically based on assessments of broad neuronal and astroglial markers. However, both neurons and astrocytes comprise heterogeneous cellular populations that can be further divided into subclasses based on unique functional and morphological characteristics. In this study, we investigated whether or not device insertion causes alterations in specific subtypes of these cells. We assessed the expression of both excitatory and inhibitory markers of neurotransmission (vesicular glutamate and GABA transporters, VGLUT1 and VGAT, respectively) surrounding single-shank Michigan-style microelectrode arrays implanted in the motor cortex of adult rats by use of quantitative immunohistochemistry. We found a pronounced shift from significantly elevated VGLUT1 within the initial days following implantation to relatively heightened VGAT by the end of the 4-wk observation period. Unexpectedly, we observed VGAT positivity in a subset of reactive astrocytes during the first week of implantation, indicating heterogeneity in early-responding encapsulating glial cells. We coupled our VGLUT1 data with the evaluation of a second marker of excitatory neurons (CamKiiα); the results closely paralleled each other and underscored a progression from initially heightened to subsequently weakened excitatory tone in the neural tissue proximal to the implanted electrode interface (within 40 μm). Our results provide new evidence for subtype-specific remodeling surrounding brain implants that inform observations of suboptimal integration and performance. NEW & NOTEWORTHY We report novel changes in the local expression of excitatory and inhibitory synaptic markers surrounding microelectrode arrays implanted in the motor cortex of rats, where a progressive shift toward increased inhibitory tone was observed over the 4-wk observation period. The result was driven by declining glutamate transporter expression (VGLUT1) in parallel with increasing GABA transporter expression (VGAT) over time, where a reactive VGAT+ astroglial subtype made an unexpected contribution to our findings.

Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs

2009 ◽  
Vol 109 ◽  
pp. 139-144 ◽  
Author(s):  
Karsten K. Madsen ◽  
Rasmus P. Clausen ◽  
Orla M. Larsson ◽  
Povl Krogsgaard-Larsen ◽  
Arne Schousboe ◽  
...  
Keyword(s):  
Gaba Transporters
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