Probing the Mode of Neurotransmitter Binding to GABA Receptors Using Selectively Fluorinated GABA Analogues

2015 ◽  
Vol 68 (1) ◽  
pp. 23 ◽  
Author(s):  
Nathan Absalom ◽  
Izumi Yamamoto ◽  
David O'Hagan ◽  
Luke Hunter ◽  
Mary Chebib
Keyword(s):  
Gaba Receptors ◽  
Organic Molecules ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Binding Modes ◽  
Stereoelectronic Effects ◽  
Natural Ligand ◽  
Gaba Analogues ◽  
Gabac Receptors

Stereoselective fluorination is a useful technique for controlling the conformations of organic molecules. This concept has been exploited to create conformationally biased analogues of the neurotransmitter gamma-aminobutyric acid (GABA). Mono- and di-fluorinated GABA analogues are found to adopt different conformations, due to subtle stereoelectronic effects associated with the C–F bond. These conformationally biased GABA analogues exhibit different shape-dependent selectivity patterns towards GABAA, GABAB, and GABAC receptors, providing valuable information on the binding modes of the natural ligand at these medicinally important targets.

scholarly journals Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus

2014 ◽  
Vol 369 (1654) ◽  
pp. 20130602 ◽  
Author(s):  
Simon Höft ◽  
Stephanie Griemsmann ◽  
Gerald Seifert ◽  
Christian Steinhäuser
Keyword(s):  
Ampa Receptors ◽  
Indirect Effects ◽  
Gaba Receptors ◽  
Brain Regions ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Functional Heterogeneity ◽  
Rt Pcr ◽  
Ventrobasal Thalamus ◽  
The Impact

Astrocytes may express ionotropic glutamate and gamma-aminobutyric acid (GABA) receptors, which allow them to sense and to respond to neuronal activity. However, so far the properties of astrocytes have been studied only in a few brain regions. Here, we provide the first detailed receptor analysis of astrocytes in the murine ventrobasal thalamus and compare the properties with those in other regions. To improve voltage-clamp control and avoid indirect effects during drug applications, freshly isolated astrocytes were employed. Two sub-populations of astrocytes were found, expressing or lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptor-bearing astrocytes displayed a lower Kir current density than cells lacking the receptors. In contrast, all cells expressed GABA A receptors. Single-cell RT-PCR was employed to identify the receptor subunits in thalamic astrocytes. Our findings add to the emerging evidence of functional heterogeneity of astrocytes, the impact of which still remains to be defined.

Molecular Targets of Cannabinoids Associated with Depression

2021 ◽  
Vol 28 ◽  
Author(s):  
Pradeep Paudel ◽  
Samir Ross ◽  
Xing-Cong Li
Keyword(s):  
Gaba Receptor ◽  
Rational Design ◽  
Cannabinoid Receptors ◽  
Molecular Targets ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Binding Modes ◽  
Novel Therapeutic Strategies ◽  
New Treatments ◽  
Synthetic Derivatives

: Novel therapeutic strategies are needed to address depression, a major neurological disorder affecting hundreds of millions of people worldwide. Cannabinoids and their synthetic derivatives have demonstrated numerous neurological activities and may potentially be developed into new treatments for depression. This review highlights cannabinoid (CB) receptors, monoamine oxidase (MAO), N-methyl-D-aspartate (NMDA) receptor, gamma-aminobutyric acid (GABA) receptor, and cholecystokinin (CCK) receptor as key molecular targets of cannabinoids that are associated with depression. The anti-depressant activity of cannabinoids and their binding modes with cannabinoid receptors are discussed, providing insights into rational design and discovery of new cannabinoids or cannabimimetic agents with improved druggable properties.

The Effects of Agonists of Ionotropic GABAAand Metabotropic GABABReceptors on Learning

2009 ◽  
Vol 12 (1) ◽  
pp. 12-20 ◽  
Author(s):  
Evgeniya A. Zyablitseva ◽  
Nikolay S. Kositsyn ◽  
Galina I. Shul'gina
Keyword(s):  
Affect Regulation ◽  
Gaba Receptors ◽  
Conditioned Inhibition ◽  
Early Stage ◽  
Dominant Role ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Internal Inhibition ◽  
Selective Agonist ◽  
The Brain

The research described here investigates the role played by inhibitory processes in the discriminations made by the nervous system of humans and animals between familiar and unfamiliar and significant and nonsignificant events. This research compared the effects of two inhibitory mediators of gamma-aminobutyric acid (GABA): 1) phenibut, a nonselective agonist of ionotropic GABAAand metabotropic GABABreceptors and 2) gaboxadol a selective agonist of ionotropic GABAAreceptors on the process of developing active defensive and inhibitory conditioned reflexes in alert non-immobilized rabbits. It was found that phenibut, but not gaboxadol, accelerates the development of defensive reflexes at an early stage of conditioning. Both phenibut and gaboxadol facilitate the development of conditioned inhibition, but the effect of gaboxadol occurs at later stages of conditioning and is less stable than that of phenibut. The earlier and more stable effects of phenibut, as compared to gaboxadol, on storage in memory of the inhibitory significance of a stimulus may occur because GABABreceptors play the dominant role in the development of internal inhibition during an early stage of conditioning. On the other hand this may occur because the participation of both GABAAand GABABreceptors are essential to the process. We discuss the polyfunctionality of GABA receptors as a function of their structure and the positions of the relevant neurons in the brain as this factor can affect regulation of various types of psychological processes.

scholarly journals HPLC-Based Activity Profiling for GABAA Receptor Modulators in Murraya exotica

2019 ◽  
Vol 14 (1) ◽  
pp. 1934578X1901400
Author(s):  
Nova Syafni ◽  
Fahimeh Moradi-Afrapoli ◽  
Ombeline Danton ◽  
Anke Wilhelm ◽  
Marco Stadler ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Xenopus Oocyte ◽  
Aminobutyric Acid ◽  
Xenopus Laevis Oocytes ◽  
Gamma Aminobutyric Acid ◽  
Activity Assay ◽  
Chloride Currents ◽  
Activity Profiling ◽  
Murraya Exotica ◽  
Receptor Modulators

A dichloromethane extract from twigs and leaves of Murraya exotica produced allosteric potentiation of gamma aminobutyric acid (GABA) induced chloride currents in a microelectrode assay in Xenopus laevis oocytes expressing GABA receptors of α1, β2, γ2s subunit composition. The activity was tracked by HPLC-based activity profiling utilizing a zebrafish locomotor activity assay. Osthol (9) was identified as the main active compound. In addition, five other coumarins and four flavonols were identified. Osthol (9) and structurally related coumurrayin (10) were tested in the Xenopus oocyte assay. Compound 9 potentiated GABAA-induced chloride currents by 487 ± 42%, with an EC50 of 46 ± 10 μM, while 10 showed negligible effects on chloride currents. In silico evaluation of physicochemical properties showed that 9 and 10 had properties that are favorable for oral bioavailability and BBB permeability.

The pharmacology of gamma-aminobutyric acid and acetylcholine receptors at the echinoderm neuromuscular junction

2001 ◽  
Vol 204 (5) ◽  
pp. 887-896 ◽  
Author(s):  
C.L. Devlin
Keyword(s):  
Neuromuscular Junction ◽  
Gaba Receptors ◽  
Muscle Fibers ◽  
The Body ◽  
Aminobutyric Acid ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Rhythmic Contractions ◽  
Ach Receptors

This review describes the various subtypes of gamma-aminobutyric acid (GABA) receptors found at the echinoderm neuromuscular junction (NMJ), based on pharmacological and physiological studies. The review focuses mainly on holothurian GABA receptors at the NMJ located between the radial nerve and longitudinal muscle of the body wall (LMBW) and compares them to GABA receptors described at other echinoderm NMJs. Since a primary action of GABA on the holothurian LMBW is to modulate contractile responses to the excitatory neurotransmitter, acetylcholine (ACh), the pharmacology of echinoderm nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChRs) is also addressed. GABA responses have been described in the asteroids, echinoids and holothuroids but not in the other echinoderm classes. Some actions of GABA on echinoderm muscle include regulation of basal tone and spontaneous rhythmic contractions and modulation of cholinergic responses. Both GABA A and B receptor subtypes are present at the echinoderm NMJ, a feature also common to the arthropods, molluscs and chordates. Echinoderm GABA A receptors may mediate the excitatory responses to GABA. The GABA A receptor antagonist bicuculline has a paradoxical effect on contractility, stimulating large protracted contractions of the LMBW. The GABA A agonist muscimol potentiates cholinergic contractions of the holothurian LMBW. Another population of GABA receptors is inhibitory and is sensitive to the GABA B agonist baclofen and GABA B antagonists phaclofen and 2-OH-saclofen. The pre- and/or postsynaptic location of the GABA A and B receptors is not currently known. The folded GABA analogue 4-cis-aminocrotonic acid has no effect on the contractility of the holothurian LMBW so GABA C receptors are probably lacking in this preparation. Pharmacological studies have shown that distinct nAChRs and mAChRs are colocalized in numerous echinoderm muscle preparations. Most recently, nAChR agonists were used to characterize pharmacologically receptors at the holothurian LMBW that bind ACh. Nicotinic AChRs with unique pharmacological profiles are localized both pre- and postsynaptically at this NMJ, where their physiological action is to enhance muscle tone. Muscarinic agonists also have excitatory actions on the LMBW but their action is to stimulate phasic, rhythmic contractions of the muscle. The location of mAChRs at the echinoderm NMJ, however, is unknown.Since most of the studies described in the present review have used whole-mount preparations consisting largely of a combination of muscle fibers, neurons and connective tissue, it is extremely difficult to determine pharmacologically the exact location of the various receptor subtypes. Additional electrophysiological studies on isolated neurons and muscle fibers are therefore required to clearly define extra-, pre- and/or postsynaptic sites for the receptor subtypes at the echinoderm NMJ.

Studies of the role of gamma-aminobutyric acid in the hypothalamic control of feed intake in sheep

1985 ◽  
Vol 63 (10) ◽  
pp. 1297-1301 ◽  
Author(s):  
C. L. Girard ◽  
J. R. Seoane ◽  
J. J. Matte
Keyword(s):  
Dose Response ◽  
Feed Intake ◽  
Gaba Receptors ◽  
Response Curve ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Gaba Antagonists ◽  
Gaba Agonist ◽  
Hypothalamic Control

Fourteen sheep were used to study the role of gamma-aminobutyric acid (GABA) on the hypothalamic control of feed intake. Injections (1 μL) of pentobarbital (262 nmol) into preoptic and paraventricular areas induced feeding in satiated sheep. Injections of GABA into the same loci gave variable results, probably because the neuronal and glial uptake of GABA limits its effects. Muscimol, a GABA agonist with a higher affinity for postsynaptic GABA receptors than GABA, injected at doses from 0 to 0.750 nmol, gave a cubic dose–response curve; the highest feed intake was measured at 0.5 nmol. The response induced by muscimol was blocked by preinjections of two GABA antagonists, picrotoxin and bicuculline, with picrotoxin being more effective than bicuculline. Muscimol responsive loci were identified mainly in the preoptic, paraventricular, and anterior hypothalamus. The data suggests that neurons sensitive to gamma-aminobutyric acid may be implicated in the control of feed intake in sheep.

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

1981 ◽  
Vol 51 (5) ◽  
pp. 1278-1286 ◽  
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.

Fermented date residue extract mix containing gamma-aminobutyric acid augments the immune function of mouse splenocytes

2021 ◽  
Author(s):  
Keiyu Hattori ◽  
Yoshinari Yamamoto ◽  
Sotaro Fujii ◽  
Thanutchaporn Kumrungsee ◽  
Momoko Hasegawa ◽  
...  
Keyword(s):  
Immune Function ◽  
Gaba Receptors ◽  
Lactobacillus Brevis ◽  
Aminobutyric Acid ◽  
Palm Tree ◽  
Gamma Aminobutyric Acid ◽  
Mouse Splenocytes ◽  
Tnf Α ◽  
Exogenous Addition ◽  
Necrosis Factor

Abstract An extract of date (fruit of a palm tree) residue plus food-grade glutamate, acetic acid, and yeast extract (date residue extract mix, DREM) has been successfully fermented with using Lactobacillus brevis JCM 1059T to produce gamma-aminobutyric acid (GABA). Here, mouse splenocytes were found to be viable when supplemented with DREM and fermented DREM containing GABA (fDREM). The addition of DREM and fDREM resulted in secretion of tumor necrosis factor (TNF)-α from the splenocytes, fDREM being more effective than DREM. The TNF-α secretion with DREM was elevated by exogenous addition of GABA and that with fDREM was in part mediated via A-type GABA receptors. Contrary to general understanding of the suppressive effects of GABA on various biological functions, our findings suggest that GABA-containing fDREM arguments the immune function as a food and pharmaceutical material.

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