The physiological properties and therapeutic potential of α5-GABAA receptors

2009 ◽  
Vol 37 (6) ◽  
pp. 1334-1337 ◽  
Author(s):  
Loren J. Martin ◽  
Robert P. Bonin ◽  
Beverley A. Orser
Keyword(s):  
Science Fiction ◽  
Gabaa Receptors ◽  
Therapeutic Potential ◽  
Memory Performance ◽  
Aminobutyric Acid ◽  
Pharmacological Properties ◽  
Physiological Properties ◽  
Drug Treatments ◽  
Subtype A ◽  
Memory Enhancing

The notion that drug treatments can improve memory performance has moved from the realm of science fiction to that of serious investigation. A popular working hypothesis is that cognition can be improved by altering the balance between excitatory and inhibitory neurotransmission. This review focuses on the unique physiological and pharmacological properties of GABAARs [GABA (γ-aminobutyric acid) subtype A receptors] that contain the α5 subunit (α5-GABAAR), as these receptors serve as candidate targets for memory-enhancing drugs.

scholarly journals Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats

2014 ◽  
Vol 306 (7) ◽  
pp. F781-F789 ◽  
Author(s):  
Zhiying Xiao ◽  
Jeremy Reese ◽  
Zeyad Schwen ◽  
Bing Shen ◽  
Jicheng Wang ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Bladder Capacity ◽  
Aminobutyric Acid ◽  
Saline Control ◽  
Receptor Subtype ◽  
High Dose ◽  
Multiple Threshold ◽  
Bladder Activity ◽  
Subtype A

Picrotoxin, an antagonist for γ-aminobutyric acid receptor subtype A (GABAA), was used to investigate the role of GABAA receptors in nociceptive and nonnociceptive reflex bladder activities and pudendal inhibition of these activities in cats under α-chloralose anesthesia. Acetic acid (AA; 0.25%) was used to irritate the bladder and induce nociceptive bladder overactivity, while saline was used to distend the bladder and induce nonnociceptive bladder activity. To modulate the bladder reflex, pudendal nerve stimulation (PNS) was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. AA irritation significantly ( P < 0.01) reduced bladder capacity to 34.3 ± 7.1% of the saline control capacity, while PNS at 2T and 4T significantly ( P < 0.01) increased AA bladder capacity to 84.0 ± 7.8 and 93.2 ± 15.0%, respectively, of the saline control. Picrotoxin (0.4 mg it) did not change AA bladder capacity but completely removed PNS inhibition of AA-induced bladder overactivity. Picrotoxin (iv) only increased AA bladder capacity at a high dose (0.3 mg/kg) but significantly ( P < 0.05) reduced 2T PNS inhibition at low doses (0.01–0.1 mg/kg). During saline cystometry, PNS significantly ( P < 0.01) increased bladder capacity to 147.0 ± 7.6% at 2T and 172.7 ± 8.9% at 4T of control capacity, and picrotoxin (0.4 mg it or 0.03–0.3 mg/kg iv) also significantly ( P < 0.05) increased bladder capacity. However, picrotoxin treatment did not alter PNS inhibition during saline infusion. These results indicate that spinal GABAA receptors have different roles in controlling nociceptive and nonnociceptive reflex bladder activities and in PNS inhibition of these activities.

scholarly journals Etomidate Targets α5γ-Aminobutyric Acid Subtype A Receptors to Regulate Synaptic Plasticity and Memory Blockade

2009 ◽  
Vol 111 (5) ◽  
pp. 1025-1035 ◽  
Author(s):  
Loren J. Martin ◽  
Gabriel H. T. Oh ◽  
Beverley A. Orser
Keyword(s):  
Synaptic Plasticity ◽  
High Frequency ◽  
Memory Performance ◽  
Long Term Potentiation ◽  
Aminobutyric Acid ◽  
High Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation ◽  
Subtype A

Background The memory-blocking properties of general anesthetics have recently received considerable attention because of concerns related to intraoperative awareness and postoperative cognitive dysfunction. The goal of this study was to identify the mechanisms by which gamma-aminobutyric acid subtype A receptors that contain the alpha5 subunit (alpha5GABAARs) induce memory-blockade by etomidate and a pharmacologic strategy to reverse this impairment. Methods The effects of etomidate and the alpha5GABAAR-preferring inverse agonist L-655,708 on the plasticity of glutamatergic excitatory transmission in hippocampal slices and behavioral memory for spatial navigational and fear-associated memory tasks were studied in wild-type and null mutant mice for the gene that encodes the alpha5 subunit (Gabra5-/- mice). Long-term potentiation of field excitatory postsynaptic potentials was induced in CA1 pyramidal neurons following high-frequency stimulation of Schaffer collaterals. Memory performance was studied in contextual, cued, and trace fear conditioning assays and the Morris water maze. Results Robust synaptic plasticity induced by high-frequency stimulation and memory performance for contextual fear and spatial navigational memory were not influenced by a decrease in the function of alpha5GABAARs. Nevertheless, etomidate, via an increase in alpha5GABAAR activity, completely blocked long-term potentiation and impaired memory performance, and these effects were reversed by pretreatment with L-655,708. Conclusions The results provide the first proof of concept that memory blockade by a general anesthetic can be reversed by inhibiting the function of alpha5GABAARs. The findings suggest a mechanism and model for awareness during anesthesia.

GABAA receptors: Various stoichiometrics of subunit arrangement in α1β3 and α1β3ε receptors

2018 ◽  
Vol 24 (17) ◽  
pp. 1839-1844 ◽  
Author(s):  
Ahmad Tarmizi Che Has ◽  
Mary Chebib
Keyword(s):  
Central Nervous System ◽  
Gabaa Receptors ◽  
Binding Sites ◽  
New Drugs ◽  
Pharmacological Properties ◽  
Receptor Complex ◽  
The Third ◽  
Γ Subunit ◽  
Subunit Stoichiometry ◽  
The Central Nervous System

GABAA receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including α1-6, β1-3, γ1-3, δ, ε, π, θ and ρ1-3. The majority of receptors are comprised of α, β and γ or δ subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are α1βγ2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to αβγ, the binary αβ receptors lack a benzodiazepine α-γ2 interface. In pentameric αβ receptors, the third subunit is replaced with either an α1 or a β3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2α:3β or 3α:2β. The consequence of this is that 3α:2β receptors contain an α-α interface whereas 2α:3β receptors contain a β-β interface. Apart from the replacement of γ by α1 or β3 in binary receptors, the incorporation of ε subunit into GABAA receptors might be more complicated. As the ε subunit is not only capable of substituting the γ subunit, but also replacing the α/β subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs.

Exploring the Chemistry and Therapeutic Potential of Triazoles: A Comprehensive Literature Review

2019 ◽  
Vol 19 (16) ◽  
pp. 1298-1368 ◽  
Author(s):  
Ankit Jain ◽  
Poonam Piplani
Keyword(s):  
Oxidative Stress ◽  
Drug Discovery ◽  
Literature Review ◽  
Structural Modification ◽  
Therapeutic Potential ◽  
Pharmacological Properties ◽  
Pharmacological Activities ◽  
Triazole Derivatives ◽  
Comprehensive Literature Review ◽  
The Common

: Triazole is a valuable platform in medicinal chemistry, possessing assorted pharmacological properties, which could play a major role in the common mechanisms associated with various disorders like cancer, infections, inflammation, convulsions, oxidative stress and neurodegeneration. Structural modification of this scaffold could be helpful in the generation of new therapeutically useful agents. Although research endeavors are moving towards the growth of synthetic analogs of triazole, there is still a lot of scope to achieve drug discovery break-through in this area. Upcoming therapeutic prospective of this moiety has captured the attention of medicinal chemists to synthesize novel triazole derivatives. The authors amalgamated the chemistry, synthetic strategies and detailed pharmacological activities of the triazole nucleus in the present review. Information regarding the marketed triazole derivatives has also been incorporated. The objective of the review is to provide insights to designing and synthesizing novel triazole derivatives with advanced and unexplored pharmacological implications.

Therapeutic perspectives of the black cumin component thymoquinone: A review

2021 ◽  
Author(s):  
Chandan Sarkar ◽  
Sarmin Jamaddar ◽  
Tawhida Islam ◽  
Milon Mondal ◽  
Muhammad Torequl Islam ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Nigella Sativa ◽  
Pharmacological Properties ◽  
Black Cumin

The dietary phytochemical thymoquinone, obtained from the black and angular seeds of Nigella sativa, is a promising monoterpenoid hydrocarbons, which has been receiving massive attention for its therapeutic potential and pharmacological properties.

scholarly journals Differential Regulation of the Postsynaptic Clustering of γ-Aminobutyric Acid Type A (GABAA) Receptors by Collybistin Isoforms

2011 ◽  
Vol 286 (25) ◽  
pp. 22456-22468 ◽  
Author(s):  
Tzu-Ting Chiou ◽  
Bevan Bonhomme ◽  
Hongbing Jin ◽  
Celia P. Miralles ◽  
Haiyan Xiao ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Type A ◽  
Differential Regulation ◽  
Aminobutyric Acid ◽  
Acid Type

scholarly journals Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia

2015 ◽  
Vol 172 (6) ◽  
pp. 1479-1493 ◽  
Author(s):  
Eelke M Bos ◽  
Harry van Goor ◽  
Jaap A Joles ◽  
Matthew Whiteman ◽  
Henri G D Leuvenink
Keyword(s):  
Hydrogen Sulfide ◽  
Therapeutic Potential ◽  
Physiological Properties

scholarly journals An association study in the Taiwan Biobank elicits the GABAA receptor genes GABRB3, GABRA5, and GABRG3 as candidate loci for sleep duration in the Taiwanese population

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sheue-Jane Hou ◽  
Shih-Jen Tsai ◽  
Po-Hsiu Kuo ◽  
Wan-Yu Lin ◽  
Yu-Li Liu ◽  
...  
Keyword(s):  
Sleep Quality ◽  
Association Study ◽  
Gabaa Receptor ◽  
Sleep Duration ◽  
Gabaa Receptors ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Bonferroni Correction ◽  
Taiwanese Population ◽  
Sleep Timing

Abstract Background Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans. Methods We determined the association between single-nucleotide polymorphisms (SNPs) in the GABAA receptor genes GABRA1, GABRA2, GABRB3, GABRA5, and GABRG3 and sleep duration, sleep quality, and sleep timing in the Taiwan Biobank with a sample of 10,127 Taiwanese subjects. There were 10,142 subjects in the original study cohort. We excluded 15 subjects with a medication history of sedative-hypnotics. Results Our data revealed an association of the GABRB3-GABRA5-GABRG3 gene cluster with sleep duration, which has not been previously identified: rs79333046 (beta = − 0.07; P = 1.21 × 10–3) in GABRB3, rs189790076 (beta = 0.92; P = 1.04 × 10–3) in GABRA5, and rs147619342 (beta = − 0.72; P = 3.97 × 10–3) in GABRG3. The association between rs189790076 in GABRA5 and sleep duration remained significant after Bonferroni correction. A variant (rs12438141) in GABRB3 was also found to act as a potential expression quantitative trait locus. Additionally, we discovered interactions between variants in the GABRB3-GABRA5-GABRG3 gene cluster and lifestyle factors, such as tea and coffee consumption, smoking, and physical activity, that influenced sleep duration, although some interactions became nonsignificant after Bonferroni correction. We also found interactions among GABRB3, GABRA5, and GABRG3 that affected sleep duration. Furthermore, we identified an association of rs7165524 (beta = − 0.06; P = 2.20 × 10–3) in GABRA5 with sleep quality and an association of rs79465949 (beta = − 0.12; P = 3.95 × 10–3) in GABRB3 with sleep timing, although these associations became nonsignificant after Bonferroni correction. However, we detected no evidence of an association of individual SNPs in GABRA1 and GABRA2. Conclusions Our results indicate that rs189790076 in GABRA5 and gene–gene interactions among GABRB3, GABRA5, and GABRG3 may contribute to sleep duration in the Taiwanese population.

scholarly journals Irreversible Inhibition of BoNT/A Protease: Unique Warhead Reactivity and Function Contingent upon a Bifunctional Approach

2021 ◽  
Author(s):  
Lewis Turner ◽  
Alexander Lund Nielsen ◽  
Lucy Lin ◽  
Sabine Pellett ◽  
Takashi Sugane ◽  
...  
Keyword(s):  
Enzyme Kinetics ◽  
Therapeutic Potential ◽  
Covalent Bond ◽  
Pharmacological Properties ◽  
Irreversible Inhibition ◽  
And Function ◽  
Chelating Compounds

We describe a comprehensive screening campaign of warheads, linked to a hydroxamate chelating anchor, for the modification of Cys165 within the BoNT/A protease. <div>Engaging thorough enzyme kinetics, we detail a remarkable proximity-driven covalent bond with an epoxide warhead, a weak electrophile; yet, one that possessed superior irreversible inhibition, and pharmacological properties, when compared to intrinsically higher reactive warheads. This directed, selective covalent bond was contingent upon the crucial hydroxamate-Zn<sup>2+ </sup>chelating interaction as exemplified by examining non-chelating compounds. </div><div>We discuss previous approaches using non-target selective cysteine-reactive warheads to modify the BoNT/A protease of which none present any therapeutic potential – our bifunctional strategy allows the use of intrinsically less reactive warheads to intercept the cysteine, which will allow for less off-target modifications of such inhibitors. Moreover, we also broach that this bifunctional approach is not a one-off strategy that we believe can be broadly translated to other metalloproteases that possess non-catalytic, yet, nucleophilic residues within the enzymes catalytic sphere. </div>

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