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PubMed1987

GABA-dependent modulation of the Cl- ionophore by steroids in rat brain.

Steroids inhibit the binding of [35S]t-butylbicyclophosphorothionate ([ 35S]TBPS) to the GABAA-benzodiazepine receptor (GBR) linked Cl- ionophore in a GABA dependent manner but not through the GABAA receptor. The most potent steroid evaluated is a naturally occurring metabolite of progesterone, 3 alpha-hydroxy,5 alpha-dihydroprogesterone with an IC50 of approximately 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [35S]TBPS labeled site to modulate the Cl- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl- ionophore complex exists.

Animals↗
PubMed2000

Immunocytochemical evidence suggesting that diamine oxidase catalyzes biosynthesis of gamma-aminobutyric acid in antropyloric gastrin cells.

gamma-Aminobutyric acid (GABA) is a neurotransmitter that also occurs in a few non-neuronal cell types, where it may serve as a paracrine modulator. GABA is biosynthesized from glutamate by glutamate decarboxylase (GAD) and from putrescine via diamine oxidase (DAO). GAD is demonstrable in several GABA-positive cell types but is undetectable in the GABA-containing gastrin cells and somatostatin cells of the antropyloric mucosa of the stomach. Using two antisera raised against synthetic peptides corresponding to two different regions of rat DAO, we now demonstrate strong reactivity for DAO in gastrin-positive cells of the rat antropyloric mucosa, whereas somatostatin-positive cells as well as other structures of the antrum are unreactive. Western blotting analysis of antrum and colon demonstrate that both antisera react with a single band of 85 kD, consistent with the predicted molecular weight of DAO. Expression of DAO mRNA in the antrum is demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR). Our results strongly indicate that gastrin cells produce GABA via DAO-catalyzed oxidation of putrescine, and experimental data moreover suggest that the biosynthesis of GABA is regulated by the prandial state. Because GABA modulates release of somatostatin, these results point to a new mechanism of paracrine interaction between gastrin cells and somatostatin cells.

Amine Oxidase (Copper-Containing)↗
PubMed2002

Circadian modulation of GABA function in the rat suprachiasmatic nucleus: excitatory effects during the night phase.

Gramicidin-perforated patch-clamp recordings were made from slices of the suprachiasmatic nucleus (SCN) of adult rats to characterize the role of gamma-amino butyric acid (GABA) in the circadian timing system. During the day, activation of GABA(A) receptors hyperpolarized the membrane of SCN neurons. During the night, however, activation of GABA(A) receptors either hyperpolarized or depolarized the membrane. These night-restricted depolarizations in a large subset of SCN neurons were capable of triggering spikes and thus appeared to be excitatory. The GABA(A) reversal potentials of SCN neurons revealed a significant day-night difference with more depolarized GABA(A) reversal potentials during the night than during the day. The emergence of depolarizing GABA(A)-mediated responses in a subset of SCN neurons at night can be ascribed to a depolarizing shift in GABA(A) reversal potential. The GABA(A) receptor antagonist bicuculline (12.5 microM) increased the spontaneous firing rate of all SCN neurons during the day, indicating that spontaneous GABA(A)-mediated inputs inhibited the SCN neurons during this period. The effect of bicuculline (12.5 microM) on the spontaneous firing rate of SCN neurons during the night was heterogeneous due to the mixture of depolarizing and hyperpolarizing GABA(A)-mediated inputs during this period. We conclude that GABA uniformly acts as an inhibitory transmitter during the day but excites a large subset of SCN neurons at night. This day-night modulation of GABAergic neurotransmission provides the SCN with a time-dependent gating mechanism that may counteract propagation of excitatory signals throughout the biological clock at day but promotes it at night.

Action Potentials↗
PubMedDate not supplied

The role of GABA in modulating the Xenopus electroretinogram.

We have recorded the electroretinogram (ERG) from the superfused eyecup of the Xenopus retina in order to assess the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and its agonists and antagonists, on individual ERG components. We found that GABA (0.5-10 mM) reduced the amplitudes of both the b- and d-waves of the Xenopus ERG. The GABA uptake blocker nipecotic acid (1 mM) had similar effects on b- and d-waves. GABA at 5 mM and 10 mM also caused an increase in the a-wave. The GABA antagonist picrotoxin (0.1-2 mM) and the GABA/a antagonist bicuculline (0.2 mM) both increased the amplitude of the b- and d-waves of the ERG. The GABA/b agonist baclofen (0.3 mM) reduced the amplitude of the ERG b-wave, enhanced the amplitude of the a-wave, and slightly reduced the amplitude and increased the peak time of the d-wave. The GABA/b antagonists phaclofen and saclofen had no reliable effects on the Xenopus ERG. Glutamate analogs known to affect specific types of retinal neurons were applied to modify the retinal circuitry and then the effects of GABA and its antagonists were examined under these modified conditions. 2-amino-4-phosphonobutyric acid (APB) increased the d-wave, and blocked the b-wave and the effect of GABA on the ERG, but not the antagonist-induced increase in the d-wave. KYN blocked the antagonist-induced increase in the b-wave, while GABA increases the amplitude of the b-wave if the d-wave has been removed by prior superfusion with kynurenic acid (KYN). N-methyl-DL-aspartate (NMDLA), which acts only in the proximal retina, reduced the amplitude of the ERG and blocked the effect of GABA and the antagonist-induced increase in ERG b- and d-waves amplitude. These results suggest that GABAergic mechanisms related to both A and B receptor types can influence the amplitude and light sensitivity of all the components of the Xenopus ERG. Since GABA is found in greatest abundance in the proximal retina, and B type of receptors are present almost exclusively there, the data suggests that most of the effects of GABA agonists and antagonists observed are dependent on proximal retinal mechanisms, and that there are separate mechanisms in the proximal retina related to the b- and the d-waves.

Animals↗
PubMed1997

Modulation of GABA receptors expressed in Xenopus oocytes by 13-L-hydroxylinoleic acid and food additives.

To study the effects of 13-L-hydroxylinoleic acid (LOH) and food additives on gamma-aminobutyric acid (GABA) receptors, ionotropic GABA receptors were expressed in Xenopus oocytes by injecting mRNAs prepared from rat whole brain. LOH, which was prepared by reduction of 13-L-hydroperoxylinoleic acid (LOOH), inhibited the response of GABA receptors in the presence of high concentrations of GABA. LOH also inhibited nicotinic acetylcholine, glycine, and kainate receptors, while it had little effect on NMDA receptors expressed in Xenopus oocytes. However, LOH potentiated the response of GABA receptors as well as LOOH in the presence of low concentrations of GABA, possibly increasing the affinity of GABA for the receptors, while linoleic acid did not. Since some modification of the compounds seemed to change their effects on GABA receptors, the responses of GABA receptors elicited by 10 microM GABA were measured in the presence of compounds with various kinds of functional groups or the structural isomers of pentanol. Potentiation of GABA receptors depended strongly on the species of functional groups and also depended on the structure of the isomers. Then effects of various kinds of food additives on GABA receptors were also examined; perfumes such as alcohols or esters potentiated the responses strongly, while hexylamine, nicotinamide, or caffeine inhibited the responses, mainly in a competitive manner, and vanillin inhibited the responses noncompetitively. These results suggest the possibility that production of LOOH and LOH, or intake of much of some food additives, modulates the neural transmission in the brain, especially through ionotropic GABA receptors and changes the frame of the human mind, as alcohol or tobacco does.

Animals↗
PubMed1991

Effect on luteinizing hormone secretion of GABA receptor modulation in the medial preoptic area at the time of proestrous luteinizing hormone surge.

Using a bilateral medial preoptic area (MPOA) infusion system in conscious female rats we have investigated the role of the GABA system in this area on the proestrous luteinizing hormone (LH) surge. Fifteen-minute blood samples for LH estimation were taken throughout the afternoon of proestrus from female rats exhibiting 4-day oestrous cycles and implanted at least 2 weeks prior with cerebral guide cannulae. Between 15:00 and 17:00 h rats received an infusion (1 microliter/30 min) of artificial cerebrospinal fluid (n = 7), 10 microM GABA (n = 6) or 10 microM bicuculline methiodide (BMI, n = 6). Animals infused with GABA failed to exhibit an LH surge, while BMI-treated animals displayed an LH surge which was not significantly different to controls. These data show that on the afternoon of proestrus, there are no tonic modulatory actions of the GABA system, acting through the GABAA receptor, on neural elements controlling the LH surge in the MPOA. If, however, GABA levels are elevated in the MPOA at this time then the LH surge is blocked. In conjunction with data from correlative studies showing a decrease in endogenous GABA release prior to the LH surge, we suggest that this fall in activity is an essential component of the LH surge mechanism.

Animals↗
PubMed2003

Synergy between retigabine and GABA in modulating the convulsant site of the GABAA receptor complex.

The molecular mechanism underlying the activity of the novel antiepileptic drug retigabine is not yet fully understood. The aim of this study was to investigate whether retigabine interacts directly with the GABA(A) receptor complex (gamma-aminobutyric acid). Receptor-binding assays were conducted using rat brain membranes. [3H]-t-Butyl-bicyclo-orthobenzoate ([3H]TBOB) was used as a tracer ligand. We determined the effects of GABA and retigabine in the presence of several concentrations of GABA on the binding of [3H]TBOB. GABA inhibited [3H]TBOB binding with an EC(50) of 4.8 microM. In the absence of GABA, retigabine inhibited [3H]TBOB with an EC(50) of 124 microM and an EC(50) of 42 microM in the presence of 2.5 microM GABA. Isobolic analysis revealed that retigabine acts in synergy with GABA in displacing [3H]TBOB. This synergy could be quantified by a molecular model in which GABA and retigabine both allosterically displace [3H]TBOB, and retigabine allosterically enhances the binding of GABA and vice versa with a factor of 4. In summary, we found that retigabine does indeed interact with a site on the GABA(A) receptor complex, and this site is positively allosterically coupled with the GABA site. This GABA-positive effect may well contribute to the clinical anticonvulsive effects of retigabine.

Animals↗
PubMed2001

Evidence for distinct conformations of the two alpha 1 subunits in diazepam-bound GABA(A) receptors.

Benzodiazepines allosterically modulate GABA(A) receptors to increase currents induced by submaximal GABA concentrations. Benzodiazepine-induced conformational changes in the transmembrane domain increase the reactivity of cysteines substituted for a subset of residues in the alpha(1) subunit M3 membrane-spanning segment. With the cysteine-substitution mutant alpha(1)F296Cbeta(1)gamma(2) we previously noted that p-chloromercuribenzenesulfonate (pCMBS(-)) modification in the presence of diazepam potentiated subsequent GABA-induced currents. In contrast, pCMBS(-) modification in the presence of GABA caused inhibition of subsequent responses. We now show that in the presence of diazepam, pCMBS(-) only reacts with the engineered cysteine in one of the two alpha subunits; whereas, in the presence of GABA, pCMBS(-) reacts with the cysteine in the other alpha subunit, or with both cysteines. This implies that the two alpha subunits have distinct conformations in the diazepam-bound state. Based on analysis of single channel kinetic data, others have hypothesized that diazepam only alters the GABA affinity of one of the two GABA binding sites. The results presented here provide structural evidence to support the hypothesis that diazepam binding only alters the conformation of one of the two alpha subunits in a GABA(A) receptor and provides new insights into the mechanism of allosteric potentiation by benzodiazepines.

Allosteric Regulation↗
PubMed1993

The spinal GABA system modulates burst frequency and intersegmental coordination in the lamprey: differential effects of GABAA and GABAB receptors.

1. The effect of spinal GABAergic neurons on the segmental neuronal network generating locomotion has been analyzed in the lamprey spinal cord in vitro. It is shown that gamma-aminobutyric acid (GABA)A- and GABAB-mediated effects influence the burst frequency and the intersegmental coordination and that the GABA system is active during normal locomotor activity. 2. Fictive locomotor activity was induced by superfusing the spinal cord with a Ringer solution containing N-methyl-D-aspartate (NMDA, 150 microM). The efferent locomotor activity was recorded by suction electrodes from the ventral roots or intracellularly from interneurons or motoneurons. If a GABA uptake blocker was added to the perfusate, the burst rate decreased. This effect was counteracted by GABAB receptor blockade by phaclofen or 2-(OH)-saclofen. If instead a GABAB receptor agonist (baclofen) was added during fictive locomotion, a depression of the burst rate occurred. It was concluded that a GABAB receptor activation due to an endogenous release of GABA caused a depression of the burst activity with a maintained well-coordinated locomotor activity. 3. If a GABAA receptor antagonist (bicuculline) is applied during fictive locomotion elicited by NMDA, a certain increase of the burst rate occurred. Conversely, if a selective GABAA agonist (muscimol) was administered, the burst rate decreased. Similarly, if the GABAA receptor activity was potentiated by activation of a benzodiazepine site by diazepam, the burst rate was reduced. If, however the GABAergic effect was first enhanced by an uptake blocker (nipecotic acid), an administration of a GABAA antagonist (bicuculline) increased the burst rate, but in addition, the burst pattern became less regular with recurrent shorter periods without clear reciprocal burst activity. The GABAA receptor activity appears important for the rate control and for permitting a regular burst pattern. 4. The intersegmental coordination in the lamprey is characterized by a rostrocaudal constant phase lag of approximately 1% of the cycle duration between the activation of consecutive segments during forward swimming. This rostrocaudal phase lag can be reversed during backward swimming, which can be induced also experimentally in the isolated spinal cord by providing a higher excitability to the caudal segments. In a split-bath configuration, a GABA uptake blocker or a GABAB agonist was administered to the rostral part of the spinal cord, which caused a reversal of the phase lag as during backward swimming. If GABAA receptors were blocked under similar conditions, the intersegmental coordination became irregular. It is concluded that an increased GABA activity in a spinal cord region can modify the intersegmental coordination.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Demonstration of a tandem pair of complement protein modules in GABA(B) receptor 1a.

We have subcloned and expressed the N-terminal portion of the recently sequenced metabotropic GABA receptor, GABA(B)R1a. This region of the receptor contains a complement protein-like amino acid sequence. The purified 140-residue recombinant protein fragment was soluble and stable. Mass spectrometry indicated formation of four disulfide bonds, as expected if two complement protein modules (CPs, also known as SCRs, Sushi domains) are formed. The circular dichroism spectrum was unusual and characteristic of CPs. Differential scanning calorimetry demonstrated a melting point (64 degrees C), and total enthalpy commensurate with two fully folded domains. We thus conclude that the 1a subtype of the GABA(B) receptor, but not the 1b subtype, contains a pair of CPs and we present a three-dimensional model of this region.

Amino Acid Sequence↗
PubMed2003

Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex.

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

Animals↗
PubMed1997

Morphine modulation of GABA- and glutamate-induced changes of ventral pallidal neuronal activity.

Microiontophoresis was used to investigate the influence of morphine on the GABA- and glutamate-evoked responses of ventral pallidal neurons recorded extracellularly from chloral hydrate-anesthetized rats. Of the GABA-sensitive neurons (50 of 69 tested) in the ventral pallidum, all displayed a decreased firing rate when GABA was applied, whereas all of the glutamate-sensitive neurons (29 of 40 tested) increased neuronal activity in the presence of glutamate. The majority of ventral pallidal cells tested (65 of 83) were sensitive to iontophoretically applied morphine, and both increases and decreases in neuronal activity were observed. The ability of morphine to alter the ratio between amino acid-evoked activity ("signal") and spontaneous firing ("noise") was used as an indicator of morphine modulation. A morphine subthreshold ejection current, i.e. one that did not change spontaneous firing rate, and a morphine ejection current that produced approximately 50% of the maximum opioid-induced neuronal response were chosen for this evaluation. When morphine was co-iontophoresed with GABA or glutamate, attenuation of the amino acid signal-to-noise ratio was generally seen, though some potentiations were observed. These changes were independent of the direction of morphine-induced changes in spontaneous firing rate. Both sub- and suprathreshold ejection currents were capable of affecting GABA- and glutamate-evoked responses. These data suggest that morphine is a robust ventral pallidal neuromodulator. As ventral pallidal amino acid activity is important in the integration of sensorimotor information, opioid modulation of amino acid transmission in the ventral pallidum may have a profound effect on this integration.

Analgesics, Opioid↗
PubMed1998

[Zinc modulation of GABA receptors expressed in Xenopus oocytes injected with carp brain poly(A)+ RNA].

Two types of GABA receptors, GABAA receptors (approximately 85%) and GABAC-like receptors (approximately 15%), were expressed in Xenopus oocytes after injection of Poly(A)+ RNA with carp (Carassius carassius) brain. Using voltage-clamp technique and pharmacological methods, the effects of zinc on the two receptors were studied. It was found that zinc modulation of both GABAA and GABAC-like receptors by zinc was inhibitory and reversible with the former being stronger than the latter as indicated by a value of IC50 of 48.4 +/- 10.1 mumol/L against 255.6 +/- 21.5 mumol/L.

Animals↗
PubMed1990

Is GABA release modulated by presynaptic excitatory amino acid receptors?

The purely GABAergic nature of spontaneous synaptic activity in cultures from the neonatal rat superior colliculus (SC) is of great advantage in investigations aimed at characterizing presynaptic factors regulating GABAergic synaptic transmission. Using SC-derived cultures it was confirmed that excitatory amino acids (EAA) can induce a marked increase in the frequency of spontaneous synaptic Cl- currents (ICl(GABA)SYN). However, this tetrodotoxin-resistant facilitation of Ca2(+)-dependent GABA release required application of EEA to several neurons (multiple cell superfusion). In contrast, no frequency increase of Icl(GABA)SYN was seen with restricted access of EAA to only one neuron and the presynaptic axonal terminals (single cell superfusion). It is therefore concluded that the strong facilitatory effect of glutamate (Glu) and kainate (KA) on GABAergic synaptic activity, as observed under the condition of multiple cell superfusion, is mediated via somatodendritic excitatory amino acid receptors (EAARs).

Action Potentials↗
PubMed1988

Presynaptic modulation of the release of GABA by GABAA receptors in pars compacta and by GABAB receptors in pars reticulata of the rat substantia nigra.

The effect of GABA agonists and antagonists on K+-stimulated [3H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABAA autoreceptors in the pars compacta and by GABAB receptors in the pars reticulata.

Animals↗
PubMed1999

Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate.

Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.

Animals↗