Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors

Nature, Journal Year: 2022, Volume and Issue: 602(7897), P. 529 - 533

Published: Feb. 9, 2022

Abstract Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits 1 . αβ, α4βδ, α6βδ α5βγ favour extrasynaptic localization, mediate an essential persistent (tonic) inhibitory conductance many regions brain 1,2 Mutations these humans are linked to epilepsy insomnia 3,4 Altered receptor function is implicated insomnia, stroke Angelman Fragile X syndromes 1,5 , drugs targeting used treat postpartum depression 6 Tonic GABAergic responses moderated avoid excessive suppression neuronal communication, can exhibit high sensitivity Zn 2+ blockade, contrast synapse-preferring α1βγ, α2βγ α3βγ 5,7–12 Here, resolve distinctive features, we determined structures predominantly αβ class. An inhibited state bound by both lethal paralysing agent α-cobratoxin 13 was comparisons with GABA–Zn GABA-bound structures. nullifies response non-competitively plugging extracellular end pore block chloride conductance. In absence signalling initially follows canonical route until it reaches pore. synaptic receptors, expansion midway activation gate limited remains closed, reflecting intrinsic low efficacy that characterizes receptor. Overall, this study explains distinct traits adopted adapt them role tonic signalling.

Language: Английский

---

Structural insights into opposing actions of neurosteroids on GABAA receptors

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 22, 2023

Abstract γ-Aminobutyric acid type A (GABA ) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs endogenous neurosteroids. subset neurosteroids GABA receptor positive allosteric modulators; one these, allopregnanolone, is only drug approved specifically for treating postpartum depression. There a consensus emerging from structural, physiological photolabeling studies as to where modulators bind, but how they potentiate activation remains unclear. Other negative receptors, their binding sites remain debated. Here we present structures synaptic bound allopregnanolone two sulfated Allopregnanolone binds at receptor-bilayer interface, potentiator site. In contrast, bind pore. MD simulations electrophysiology support mechanism by which potentiates channel activity suggest dominant neurosteroid inhibition through pore block.

Language: Английский

---

Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology

Nature, Journal Year: 2023, Volume and Issue: 622(7981), P. 195 - 201

Published: Sept. 20, 2023

Abstract Type A γ-aminobutyric acid receptors (GABA Rs) are the principal inhibitory in brain and target of a wide range clinical agents, including anaesthetics, sedatives, hypnotics antidepressants 1–3 . However, our understanding GABA R pharmacology has been hindered by vast number pentameric assemblies that can be derived from 19 different subunits 4 lack structural knowledge clinically relevant receptors. Here, we isolate native murine containing widely expressed α1 subunit elucidate their structures complex with drugs used to treat insomnia (zolpidem (ZOL) flurazepam) postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis single-molecule photobleaching experiments, uncover three major populations brain: canonical α1β2γ2 receptor two subunits, one either an α2 or α3 subunit, which single α1-containing feature more compact arrangement between transmembrane extracellular domains. Interestingly, APG is bound at α/β interface, even when not added sample, revealing important role for endogenous neurosteroids modulating Rs. Together structurally engaged lipids, produce global conformational changes throughout modify ion channel pore binding sites medications. Our data reveal assemblies, neurosteroid, thus defining landscape subtype-specific developed.

Language: Английский

---

Molecular mechanisms of the GABA type A receptor function

Quarterly Reviews of Biophysics, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition adult mammalian brains. Dysfunction this macromolecule may lead epilepsy, anxiety disorders, autism, depression, schizophrenia. GABAAR is also target for multiple physiologically clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, neurosteroids. first structure appeared 2014, but past years have brought particularly abundant surge structural data these receptors with various ligands modulators. Although open conformation remains elusive, novel information has pushed structure-function studies an unprecedented level. Electrophysiology, mutagenesis, photolabeling, silico simulations, guided by information, shed new light on molecular mechanisms functioning. main goal review present current knowledge functional properties. begins outline GABAAR, accompanied some methodological considerations, especially biophysical methods, enabling reader follow how major breakthroughs characterizing features been achieved. section provides comprehensive analysis significance specific elements GABAARs. We additionally summarize binding sites referring underpinnings their action. final chapter moves beyond examining isolated describes interactions other proteins broader context inhibitory plasticity. In section, we propose conclusion that agonist orthosteric appears rely local interactions, whereas conformational transitions bound (gating) allosteric modulation seem reflect more global phenomena involving vast portions macromolecule.

Language: Английский

---

Multifaceted Actions of Neurosteroids

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Neurosteroids modulate neuronal function and are promising therapeutic agents for neuropsychiatric disorders. Neurosteroid analogues approved treating postpartum depression of interest in other GABA-A receptors well characterized targets natural neurosteroids, but biological pathways likely relevant to mechanisms and/or off-target effects. We performed hypothesis-generating silico analyses broad vitro screens assess the range actions neurosteroids varying structural attributes. employed molecular similarity analysis network pharmacology elucidate targets. This confirmed beyond receptors. then functionally screened 19 distinct neurosteroid structures across 78 representing interconnected signaling pathways, complemented with a limited screen kinase activation. Results revealed unanticipated modulation by some selectivity. Many compounds-initiated androgen receptor translocation little or no enantioselectivity. Modulation multiple G-protein was also unexpected. ascendant treatments neuropsychiatry, their full spectrum remains unclear. virtual screening discovery approach opens new vistas exploring mechanism analogues. The multifaceted provides an unbiased, holistic exploration potential effects various platform future validation studies aid drug discovery.

Language: Английский

---

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 14

Published: Jan. 14, 2021

Diverse populations of GABA A receptors (GABA Rs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands therapeutic drugs. Deficits in R signaling underlie pathophysiology behind neurological neuropsychiatric disorders such as epilepsy, anxiety, depression. Pharmacological intervention for these relies on several drug classes that target Rs, benzodiazepines more recently neurosteroids. It has been widely demonstrated subunit composition receptor stoichiometry impact biophysical pharmacological properties Rs. However, current R-targeting drugs have limited selectivity produce their effects concomitantly with undesired side effects. Therefore, there is still a need to develop selective pharmaceuticals, well evaluate potential developing next-generation can accessory proteins associated native In this review, we briefly discuss neurosteroids use therapeutics, some pitfalls adverse We also recent advances toward understanding structure, function, pharmacology Rs focus neurosteroids, newly identified transmembrane modulate

Language: Английский

---

Neurosteroid enantiomers as potentially novel neurotherapeutics

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105191 - 105191

Published: April 20, 2023

Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These modulate major signaling systems the brain intracellular processes including inflammation, cellular stress autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which physiochemically identical to their natural counterparts except rotation polarized light. led insights how NAS interact with receptors, ion channels sites action. Certain effects show high enantioselectivity, consistent actions chiral environments likely direct interactions proteins. Other no enantioselectivity even reverse enantioselectivity. The spectrum raises possibility that these agents, once considered only as tools preclinical studies, have potential complements some cases may exceed counterparts. Here review from perspective novel neurotherapeutics.

Language: Английский

---

GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder

CNS Drugs, Journal Year: 2023, Volume and Issue: 37(8), P. 679 - 693

Published: Aug. 1, 2023

Language: Английский

---

Neurosteroids and their potential as a safer class of general anesthetics

Journal of Anesthesia, Journal Year: 2024, Volume and Issue: 38(2), P. 261 - 274

Published: Jan. 22, 2024

Abstract Neurosteroids (NS) are a class of steroids that synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, function as mediators mood. One NS, 3α-hydroxy-pregnane such allopregnanolone (AlloP) pregnanolone (Preg), inhibits neuronal excitability; these endogenous their analogues have been therapeutically applied anti-depressants, anti-epileptics general anesthetics. While many favorable properties anesthetics (e.g. rapid onset, recovery, minimal cardiorespiratory depression, neuroprotection), not currently clinical use, largely due to problems with formulation. Recent advances understanding mechanisms action improved formulations rekindled interest development sedatives In this review, synthesis mechanism will be reviewed specific emphasis on binding sites actions γ-aminobutyric acid type A (GABA ) receptors. The potential advantages sedative anesthetic agents discussed.

Language: Английский

---

Forty Years Searching for Neurosteroid Binding Sites on GABAA Receptors

Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Language: Английский

---