GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response

Gunn, Benjamin G.; Cunningham, Linda; Mitchell, Stephen J.; Swinny, Jerome D.; Lambert, Jeremy J.; Belelli, Delia

doi:10.1016/j.yfrne.2014.06.001

Cited by 129 publications

(113 citation statements)

References 313 publications

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“…Numerous expression studies using recombinant receptors indicated that receptors composed of α, β, and γ subunits form GABAA receptors with a pharmacological profile that mimic properties of the majority of native receptors. Despite the fact that the immense number of different pentameric combinations can be assembled from the pool of native protein subunits, it seems that the prevalent form of native GABAA receptors is the combination of two α, two β and a single γ, δ or ε subunit [30,31]. As mentioned before, isoform α1β2γ2 is considered as the most prevalent subtype of adult GABAA receptors, with γ2β2α1β2α1 counter-clockwise arrangement surrounding central ion pore when viewed from the synaptic cleft [32].…”

Section: Subunit Composition Determines Pharmacological Effectsmentioning

confidence: 99%

“…Drugs acting at benzodiazepine binding sites can only modulate GABAA receptors, while barbiturates, neuroactive steroids and anesthetics at higher concentrations are able to directly activate GABAA receptors in the absence of GABA [31,[59][60][61][62][63]. Binding sites for all of these drugs are allosterically coupled.…”

Section: Modulation Of Gabaa Receptors By Pharmacological Agentsmentioning

confidence: 99%

“…In general, they potently enhance function of synaptic and extrasynaptic GABAA receptors by an allosteric mechanism [31,40,166,167]. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance mainly via potentiation of GABAA receptors at low doses, and direct activation of receptor chloride channel at higher concentrations.…”

Section: Effects Of Neurosteroids At Gabaa Receptorsmentioning

confidence: 99%

“…They allosterically modulate channel opening, and at high concentrations act as GABA-mimetics and directly open the chloride channel [31,53,176]. Two discrete binding sites in the receptor's transmembrane domains have been identified that mediate the potentiating and direct activation effects of neurosteroids.…”

Section: G-protein-coupled Receptors Via Nongenomic Mechanisms Inclumentioning

confidence: 99%

“…Chisary et al [180] have shown that neurosteroids require a membranous route of access to transmembrane-domain binding sites that might have implications for the design of novel neuroactive steroids because their lipid solubility and related accessibility are probably the key determinants of receptor modulation [180]. This also suggests that by virtue of their high lipid solubility, µM concentrations of neurosteroids may be achieved locally [31]. Similarly to other binding sites, subunit assembly determines sensitivity and pharmacological effects of neuroactive steroids.…”

Section: G-protein-coupled Receptors Via Nongenomic Mechanisms Inclumentioning

confidence: 99%

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GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

108

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Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

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Section: Subunit Composition Determines Pharmacological Effectsmentioning

confidence: 99%

Section: Modulation Of Gabaa Receptors By Pharmacological Agentsmentioning

confidence: 99%

Section: Effects Of Neurosteroids At Gabaa Receptorsmentioning

confidence: 99%

Section: G-protein-coupled Receptors Via Nongenomic Mechanisms Inclumentioning

confidence: 99%

Section: G-protein-coupled Receptors Via Nongenomic Mechanisms Inclumentioning

confidence: 99%

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GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

108

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GABA Receptors and the Pharmacology of Sleep

Wisden

Franks

2017

Handbook of Experimental Pharmacology

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Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABA receptors, continue to be some of the most effective compounds to treat primary insomnia.

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Hypotalamus-Pituitary-Adrenal (HPA) Axes and Their Relationship with Stress, Mood, Personality, and Neurocognitive Functioning

Robayo

2023

Logic, Argumentation &Amp; Reasoning

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GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response

Cited by 129 publications

References 313 publications

GABA Receptors: Pharmacological Potential and Pitfalls

GABA Receptors: Pharmacological Potential and Pitfalls

GABA Receptors and the Pharmacology of Sleep

Hypotalamus-Pituitary-Adrenal (HPA) Axes and Their Relationship with Stress, Mood, Personality, and Neurocognitive Functioning

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