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PubMed2006

GABAB receptor association with the PDZ scaffold Mupp1 alters receptor stability and function.

gamma-Aminobutyric acid, type B (GABA(B)) receptors are heterodimeric G protein-coupled receptors that mediate slow inhibitory synaptic transmission in the central nervous system. To identify novel interacting partners that might regulate GABA(B) receptor (GABA(B)R) functionality, we screened the GABA(B)R2 carboxyl terminus against a recently created proteomic array of 96 distinct PDZ (PSD-95/Dlg/ZO-1 homology) domains. The screen identified three specific PDZ domains that exhibit interactions with GABA(B)R2: Mupp1 PDZ13, PAPIN PDZ1, and Erbin PDZ. Biochemical analysis confirmed that full-length Mupp1 and PAPIN interact with GABA(B)R2 in cells. Disruption of the GABA(B)R2 interaction with PDZ scaffolds by a point mutation to the carboxyl terminus of the receptor dramatically decreased receptor stability and attenuated the duration of GABA(B) receptor signaling. The effects of mutating the GABA(B)R2 carboxyl terminus on receptor stability and signaling were mimicked by small interference RNA knockdown of endogenous Mupp1. These findings reveal that GABA(B) receptor stability and signaling can be modulated via GABA(B)R2 interactions with the PDZ scaffold protein Mupp1, which may contribute to cell-specific regulation of GABA(B) receptors in the central nervous system.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Modulation of mammalian dendritic GABA(A) receptor function by the kinetics of Cl- and HCO3- transport.

1. During prolonged activation of dendritic GABAA receptors, the postsynaptic membrane response changes from hyperpolarization to depolarization. One explanation for the change in direction of the response is that opposing HCO3- and Cl- fluxes through the GABAA ionophore diminish the electrochemical gradient driving the hyperpolarizing Cl- flux, so that the depolarizing HCO3- flux dominates. Here we demonstrate that the necessary conditions for this mechanism are present in rat hippocampal CA1 pyramidal cell dendrites. 2. Prolonged GABAA receptor activation in low-HCO3- media decreased the driving force for dendritic but not somatic Cl- currents. Prolonged GABAA receptor activation in low-Cl- media containing physiological HCO3- concentrations did not degrade the driving force for dendritic or somatic HCO3- gradients. 3. Dendritic Cl- transport was measured in three ways: from the rate of recovery of GABAA receptor-mediated currents between paired dendritic GABA applications, from the rate of recovery between paired synaptic GABAA receptor-mediated currents, and from the predicted vs. actual increase in synaptic GABAA receptor-mediated currents at progressively more positive test potentials. These experiments yielded estimates of the maximum transport rate (vmax) for Cl- transport of 5 to 7 mmol l-1 s-1, and indicated that vmax could be exceeded by GABAA receptor-mediated Cl- influx. 4. The affinity of the Cl- transporter was calculated in experiments in which the reversal potential for Cl- (ECl) was measured from the GABAA reversal potential in low-HCO3- media during Cl- loading from the recording electrode solution. The calculated KD was 15 mM. 5. Using a standard model of membrane potential, these conditions are demonstrated to be sufficient to produce the experimentally observed, activity-dependent GABA(A) depolarizing response in pyramidal cell dendrites.

Animals↗
PubMed1980

Presynaptic membrane protein phosphorylation modulates the release of GABA from preloaded synaptosomes.

Incubation of rat cortical synaptosomes in the presence of 1 mM ATP markedly reduced Ca2+-dependent K+-induced release of preloaded 3H-GABA. This effect is probably dependent on phosphorylation of presynaptic membrane proteins. By contrast, the uptake of 3H-GABA by the nerve endings was not significantly affected by phosphorylation. These data suggest that membrane protein phosphorylation and dephosphorylation may form a mechanism for the presynaptic control of transmitter release.

Adenosine Triphosphate↗
PubMed2004

M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals.

KCNQ subunits encode for the M current (I(KM)), a neuron-specific voltage-dependent K+ current with a well established role in the control of neuronal excitability. In this study, by means of a combined biochemical, pharmacological, and electrophysiological approach, the role of presynaptic I(KM) in the release of previously taken up tritiated norepineprine (NE), GABA, and d-aspartate (d-ASP) from hippocampal nerve terminals (synaptosomes) has been evaluated. Retigabine (RT) (0.01-30 microm), a specific activator of I(KM), inhibited [3H]NE, [3H]d-ASP, and [3H]GABA release evoked by 9 mm extracellular K+ ([K+]e). RT-induced inhibition of [3H]NE release was prevented by synaptosomal entrapment of polyclonal antibodies directed against KCNQ2 subunits, an effect that was abolished by antibody preabsorption with the KCNQ2 immunizing peptide; antibodies against KCNQ3 subunits were ineffective. Flupirtine (FP), a structural analog of RT, also inhibited 9 mm [K+]e-induced [3H]NE release, although its maximal inhibition was lower than that of RT. Electrophysiological studies in KCNQ2-transfected Chinese hamster ovary cells revealed that RT and FP (10 microm) caused a -19 and -9 mV hyperpolarizing shift, respectively, in the voltage dependence of activation of KCNQ2 K+ channels. In the same cells, the cognition enhancer 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991) (10 microm) blocked KCNQ2 channels and prevented their activation by RT (1-10 microm). Finally, both XE-991 (10-100 microm) and tetraethylammonium ions (100 microm) abolished the inhibitory effect of RT (1 microm) on [3H]NE release. These findings provide novel evidence for a major regulatory role of KCNQ2 K+ channel subunits in neurotransmitter release from rat hippocampal nerve endings.

Aminopyridines↗
PubMed2003

Quantitative in vivo measurement of central benzodiazepine receptors in the brain of cats by use of positron-emission tomography and [11C]flumazenil.

OBJECTIVE: To map central benzodiazepine receptors (BZRs) in the brain of cats by use of positron-emission tomography (PET) and [11C]flumazenil. ANIMALS: 6 male cats that weighed between 2.0 and 3.6 kg. PROCEDURE: Brain images obtained by PET evaluation of [11C]flumazenil were superimposed on T2-weighted magnetic-resonance imaging (MRI) scans of the same cats. Detailed anatomic regions, such as the cerebral cortex, striatum, thalamus, midbrain, and cerebellum, on the PET images were evident by PET-MRI registration. Regional binding of [11C]flumazenil to BZRs was quantitatively measured by use of a model with 2 tissue compartments and 4 variables. RESULTS: The highest value for distribution volume was observed in the cerebral cortex, and the lowest value was found in the midbrain of cats. CONCLUSIONS AND CLINICAL RELEVANCE: Binding of [11C]flumazenil to BZRs in the brain of cats can be quantitatively measured by use of PET with the aid of PET-MRI registration. It is difficult to diagnose changes in these neuroreceptors within the field of current veterinary science. In the future, PET should prove useful for investigating and diagnosing brain disorders in animals in clinical settings.

Animals↗
PubMed1985

Modulation of a GABA-ergic inhibitory circuit in the in vitro hippocampus by etomidate isomers.

A pulse-paired stimulation technique was used to examine the in vitro effects of the isomers of etomidate on synaptic transmission between Schaffer collaterals and CA1 pyramidal cells in the guinea pig hippocampus. Etomidate produced a dose-related, stereospecific, reversible increase in paired-pulse inhibition. Replacement of Cl- by isethionate reversed the inhibition induced by (+)-etomidate. Together with earlier biochemical evidence, these results show that in the mammalian CNS (+)-etomidate enhances central inhibition by increasing the effectiveness of gamma-aminobutyric acid (GABA) in a chloride-dependent fashion.

Animals↗
PubMed1991

GABA agonists and omega conotoxin GVIA modulate responses to nerve activation of the perfused rat mesentery.

The modulatory actions of gamma-aminobutyric acid (GABA) receptor agonists and omega-conotoxin GVIA (CTX) on sympathetic and sensory nerves were examined on contractile responses of the perfused rat mesentery to transmural nerve stimulation (TNS). GABA and baclofen, a selective GABAB receptor agonist, significantly inhibited vasoconstrictor responses to TNS, while muscimol, a selective GABAA receptor agonist, had no effect. In the guanethidine treated and methoxamine-contracted mesentery, TNS caused a vasodilator response which was unaffected by GABA. CTX (10(-8) M) markedly suppressed the vasoconstrictor response to TNS, but did not affect vasodilator responses. These findings suggest that in the rat mesentery: (1) GABA receptors modulate the activity of sympathetic nerves via prejunctional GABAB receptors, but do not influence sensory nerves, and (2) calcium channels which participate in sympathetic nerve activation have different properties than calcium channels in capsaicin-sensitive sensory nerves.

Animals↗
PubMed1996

Opposing actions of adenosine A2a and dopamine D2 receptor activation on GABA release in the basal ganglia: evidence for an A2a/D2 receptor interaction in globus pallidus.

There is increasing evidence that adenosine (ADO) and dopamine (DA) interact directly in the basal ganglia via actions at ADO A2a and DA D2 receptors, respectively. The purpose of this study was to determine 1) the extent to which these receptors modulate endogenous GABA release in discrete regions of the rat basal ganglia and 2) whether GABA release is modulated by a direct and opposing interaction between ADO A2a and DA D2 receptors. Tissue slices of striatum (STR) containing globus pallidus (GP; STR/GP) and micropunches of STR, GP, and substantia nigra pars reticulata (SNr) were studied. Radioligand binding demonstrated that ADO A1, ADO A2a, and DA D2 receptors were present in each of the tissue preparations with the exception of SNr, in which ADO A2a receptors were not detected. Stimulation of ADO A2a receptors with CGS 21680 (1-10 nM) increased electrically stimulated GABA release in STR/GP slices and GP micropunches. Consistent with the lack of A2a receptors in SNr, CGS 21680 had no effect on GABA release from this region. In contrast, stimulation of DA D2 receptors with N-0437 (1-100 nM) inhibited evoked GABA release from STR/GP slices and both GP and SNr micropunches. The D2-mediated inhibition of GABA release in GP was abolished in the presence of CGS 21680 (10 nM). These experiments demonstrate that stimulation of ADO A2a and DA D2 receptors has opposing effects on endogenous GABA release in STR and GP. These opposing actions may explain the antagonistic interactions between ADO and DA that have been observed in behavioral studies and support the hypothesis that the striatopallidal efferent system is an important anatomical substrate for the A2a/D2 receptor interaction.

Adenosine↗
PubMed2006

Beta and gamma range EEG power-spectrum correlation with spiking discharges in DBA/2J mice absence model: role of GABA receptors.

PURPOSE: To describe the correlations between spiking pattern and EEG power spectrum frequency in DBA/2J mice, a model for murine absence seizures, after gamma-aminobutyric acid (GABA)(B) modulation. METHODS: The animals were first tested with the GABA(B) agonist l-baclofen followed by the GABA(B) antagonist SCH 50911. Moreover, digital EEGs recorded under experimental conditions were processed at baseline and 10 and 20 min after l-baclofen injection. This procedure was followed by injection of the GABA(B) antagonist SCH50911 and by an additional EEG evaluation at 10 and 20 min from drug administration. The power spectra analysis of signals was obtained for delta (0.5-3 Hz), theta (3.5-7.5 Hz), alpha (8-12 Hz), beta (13-20 Hz), and gamma (21-50 Hz) frequencies. RESULTS: The spiking pattern and power spectrum of beta activity was increased by 80%), whereas gamma power increased (correlation, 0.92; p < 0.001). The remaining frequency bands were unaffected. CONCLUSIONS: This study confirms the potential of GABA(B) antagonists in contrasting seizure absence in rodent models and suggests the application of drugs with a similar mechanism in humans. In addition, because GABA(B) antagonists not only contrast seizure in rodent models of absence but also improve "cognitive" performance, it could be hypothesized that gamma increase, correlated with optimized cortical binding during coherent percepts, may produce potential cognition-enhancing effects.

Alpha Rhythm↗
PubMed2004

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice.

RATIONALE: It has been suggested that GABA(B) receptors may be part of a neural substrate mediating some of the effects of ethanol. OBJECTIVE: The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA(B) receptors. METHODS: Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice. RESULTS: Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance. CONCLUSIONS: Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA(B) drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.

Animals↗
PubMed2004

GABAA receptors modulate cannabinoid-evoked hypothermia.

Cannabinoids evoke hypothermia by stimulating central CB(1) receptors. GABA induces hypothermia via GABA(A) or GABA(B) receptor activation. CB(1) receptor activation increases GABA release in the hypothalamus, a central locus for thermoregulation, suggesting that cannabinoid and GABA systems may be functionally linked in body temperature regulation. We investigated whether GABA receptors modulate the hypothermic actions of [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one] (WIN 55212-2), a selective cannabinoid agonist, in male Sprague-Dawley rats. WIN 55212-2 (2.5 mg/kg im) produced a rapid hypothermia that peaked 45-90 min postinjection. The hypothermia was attenuated by bicuculline (2 mg/kg ip), a GABA(A) antagonist. However, SCH 50911 (1-10 mg/kg ip), a GABA(B) blocker, did not antagonize the hypothermia. Neither bicuculline (2 mg/kg) nor SCH 50911 (10 mg/kg) by itself altered body temperature. We also investigated a possible role for CB(1) receptors in GABA-generated hypothermia. Muscimol (2.5 mg/kg ip), a GABA(A) agonist, or baclofen (5 mg/kg ip), a GABA(B) agonist, evoked a significant hypothermia. Blockade of CB(1) receptors with SR141716A (2.5 mg/kg im) did not antagonize muscimol- or baclofen-induced hypothermia, indicating that GABA-evoked hypothermia does not contain a CB(1)-sensitive component. Our results implicate GABA(A) receptors in the hypothermic actions of cannabinoids and provide further evidence of a functional link between cannabinoid and GABA systems.

Animals↗
PubMed1998

Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study.

The role of GABA receptors in regulating the mesolimbic dopamine (DA) system and drug reinforced behaviors has not been well characterized. Using fast-cyclic voltammetry, the effects of specific GABA receptor modulation on DA release in the nucleus accumbens (NAcc) and heroin self-administration (SA) behavior was investigated. The GABAA agonist muscimol, administered either intravenously or directly into the ventral tegmental area (VTA), significantly increased DA release in the NAcc in 7 of the 10 rats tested. DA release decreased in the remaining three rats; both effects were blocked by pretreatment with the GABAA receptor antagonist bicuculline. In contrast, the GABAB agonist baclofen decreased, while 2-OH-saclofen (a GABAB antagonist) increased DA release in the NAcc. However, when VTA GABAB receptors were previously activated or inactivated by microinjections of baclofen or 2-OH-saclofen, systemic injections of muscimol caused an inhibition of NAcc DA release. These results suggest that GABAA receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABAA determined by the net effect of both direct inhibition and indirect disinhibition of DA neurons. Finally, although a DA releaser, muscimol was neither self-administered in drug naive rats, nor did it substitute for heroin in rats previously trained to self-administer heroin, suggesting that GABAA receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABAA receptors on both tegmental DA and non-DA neurons.

Animals↗
PubMed2004

The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands.

The sodium- and chloride-dependent gamma-aminobutyric acid (GABA) transporter GAT-1 is the first identified member of a family of transporters, which maintain low synaptic neurotransmitter levels and thereby enable efficient synaptic transmission. To obtain evidence for the idea that the highly conserved transmembrane domain I (TMD I) participates in the permeation pathway, we have determined the impact of impermeant methanethiosulfonate (MTS) reagents on cysteine residues engineered into this domain. As a background the essentially insensitive but fully active C74A mutant has been used. Transport activity of mutants with a cysteine introduced cytoplasmic to glycine 63 is largely unaffected and is resistant to the impermeant MTS reagents. Conversely, transport activity in mutants extracellular to glycine 63 is strongly impacted. Nevertheless, transport activity could be measured in all but three mutants: G65C, N66C, and R69C. In each of the six active cysteine mutants the activity is highly sensitive to the impermeant MTS reagents. This sensitivity is potentiated by sodium in L64C, F70C, and Y72C, but is protected in V67C and P71C. GABA protects in L64C, W68C, F70C, and P71C. The non-transportable GABA analogue SKF100330A also protects in L64C, W68C, and P71C as well as V67C, but strikingly potentiates inhibition in F70C. Although cysteine substitution in this region may have perturbed the native structure of GAT-1, our observations, taken together with the recently published accessibility study on the related serotonin transporter (Henry, L. K., Adkins, E. M., Han, Q., and Blakely, R. D. (2003) J. Biol. Chem. 278, 37052-37063), suggest that the extracellular part of TMD I is conformationally sensitive, lines the permeation pathway, and forms a more extended structure than expected from a membrane-embedded alpha-helix.

Carrier Proteins↗