GABA A Receptors and the Diversity in their Structure and Pharmacology

Chua, Han Chow; Chebib, Mary

doi:10.1016/bs.apha.2017.03.003

Cited by 128 publications

(129 citation statements)

References 145 publications

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“…Different subtypes of GABA A Rs are generated by a coassembly of the α1‐6, β1‐3, γ1‐3, δ, ε, θ, π, and ρ1‐3 subunits . Strong evidence supports a model in which subunit composition confers a distinctive cellular distribution, functional properties, and the specific effect of allosteric modulators like benzodiazepines or neurosteroids . In brain regions, including the striatum, synaptic neurotransmission mediating phasic inhibition is linked to GABA A Rs composed of α1, α2, or α3 in combination with β and γ2 subunits (Figure A).…”

Section: Structure and Function Of Gabaarsmentioning

confidence: 99%

“…45 Strong evidence supports a model in which subunit composition confers a distinctive cellular distribution, functional properties, and the specific effect of allosteric modulators like benzodiazepines or neurosteroids. 36,45,46 In brain regions, including the striatum, synaptic neurotransmission mediating phasic inhibition is linked to GABA A Rs composed of α1, α2, or α3 in combination with β and γ2 subunits ( Figure 1A). The substitution of an α5 by an α1-3 or a δ by a γ2 subunit has been shown to form extrasynaptic receptors ( Figure 1B) mediating tonic inhibition.…”

Section: G Abaer Gic Neurotr Ans Miss Ionmentioning

confidence: 99%

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Alteration of GABAergic neurotransmission in Huntington's disease

Garret

Chazalon

et al. 2018

CNS Neurosci Ther

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Hereditary Huntington's disease (HD) is characterized by cell dysfunction and death in the brain, leading to progressive cognitive, psychiatric, and motor impairments. Despite molecular and cellular descriptions of the effects of the HD mutation, no effective pharmacological treatment is yet available. In addition to well-established alterations of glutamatergic and dopaminergic neurotransmitter systems, it is becoming clear that the GABAergic systems are also impaired in HD. GABA is the major inhibitory neurotransmitter in the brain, and GABAergic neurotransmission has been postulated to be modified in many neurological and psychiatric diseases. In addition, GABAergic neurotransmission is the target of many drugs that are in wide clinical use. Here, we summarize data demonstrating the occurrence of alterations of GABAergic markers in the brain of HD carriers as well as in rodent models of the disease. In particular, we pinpoint HD-related changes in the expression of GABA receptors (GABA Rs). On the basis that a novel GABA pharmacology of GABA Rs established with more selective drugs is emerging, we argue that clinical treatments acting specifically on GABAergic neurotransmission may be an appropriate strategy for improving symptoms linked to the HD mutation.

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Section: Structure and Function Of Gabaarsmentioning

confidence: 99%

Section: G Abaer Gic Neurotr Ans Miss Ionmentioning

confidence: 99%

Alteration of GABAergic neurotransmission in Huntington's disease

Garret

Chazalon

et al. 2018

CNS Neurosci Ther

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“…Particularly troubling has been the polymodal nature of anesthetics: these relatively small, low-affinity, nonspecific drugs are likely to bind multiple sites with varying affinities and efficacies, producing combinatorial effects unique to each receptor [193]. Potential variability in anesthetic sensitivities is further inflated by the presence of multiple homologous, but nonidentical, subunits in most human pLGICs, producing a wide range of possible binding sites across the proteome [194, 195]. Specific amino acid residues have been implicated in anesthetic binding by a variety of functional methods, particularly electrophysiology and photolabeling of engineered receptor variants, as reviewed elsewhere [e.g.…”

Section: Key Questions Subject To Interdisciplinary Study In Ion Tmentioning

confidence: 99%

Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport

Howard¹,

Carnevale²,

Delemotte³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Ion translocation across biological barriers is a fundamental requirement for life. In many cases, controlling this process-for example with neuroactive drugs-demands an understanding of rapid and reversible structural changes in membrane-embedded proteins, including ion channels and transporters. Classical approaches to electrophysiology and structural biology have provided valuable insights into several such proteins over macroscopic, often discontinuous scales of space and time. Integrating these observations into meaningful mechanistic models now relies increasingly on computational methods, particularly molecular dynamics simulations, while surfacing important challenges in data management and conceptual alignment. Here, we seek to provide contemporary context, concrete examples, and a look to the future for bridging disciplinary gaps in biological ion transport. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain.

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“…Continuing our study on GABA A -Rs subtype ligands, we focalized our attention on compounds with pyrazolo [1,5-a] quinazoline (PQ) scaffold as 5-deaza analogues of the potent pyrazolo [5,1-c] [1,2,4]benzotriazines, previously identified by our research group as high affinity GABA A -R subtype ligands [10,13,16,17]. We first synthesized pyrazolo[1,5-a]quinazoline and 4,5-dihydropyrazolo [1,5-a] quinazoline variously substituted at 3-position and/or 8-position [18,19].…”

Section: Introductionmentioning

confidence: 99%

New 3,6‐Disubstituted Pyrazolo[1,5‐a]quinazolines as Ligands to GABA_A Receptor Subtype

Guerrini

Crocetti

Daniele

et al. 2019

Journal of Heterocyclic Chem

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A new series of 3,6‐disubstituted pyrazolo[1,5‐a]quinazolines (PQs) and their 4,5‐dihydro derivatives as isomer of the potent 3,8‐PQ previously reported by us as high affine GABAA receptor subtype ligands, have been synthesized and evaluated. These new compounds have been obtained exploiting a different synthetic pathway with respect to the corresponding 3,8‐disubstituted isomers, proposing again the same groups present in the reference 3,8‐PQ. The movement of the substituents from position 8 to position 6 is detrimental for binding recognition, suggesting that the substituents at position 6 are not properly oriented to form adequate interaction with hydrogen bond point and lipophilic area in the receptor protein, as demonstrated in molecular modeling studies.

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GABA A Receptors and the Diversity in their Structure and Pharmacology

Cited by 128 publications

References 145 publications

Alteration of GABAergic neurotransmission in Huntington's disease

Alteration of GABAergic neurotransmission in Huntington's disease

Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport

New 3,6‐Disubstituted Pyrazolo[1,5‐a]quinazolines as Ligands to GABA_A Receptor Subtype

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GABA A Receptors and the Diversity in their Structure and Pharmacology

Cited by 128 publications

References 145 publications

Alteration of GABAergic neurotransmission in Huntington's disease

Alteration of GABAergic neurotransmission in Huntington's disease

Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport

New 3,6‐Disubstituted Pyrazolo[1,5‐a]quinazolines as Ligands to GABAA Receptor Subtype

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Product

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New 3,6‐Disubstituted Pyrazolo[1,5‐a]quinazolines as Ligands to GABA_A Receptor Subtype