GABAA Receptor Structure–Function Studies: A Reexamination in Light of New Acetylcholine Receptor Structures

Akabas, Myles H.

doi:10.1016/s0074-7742(04)62001-0

Cited by 46 publications

(35 citation statements)

References 231 publications

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“…Because residue ␣ 1 Ser269 is oriented toward the center of the four-helix bundle, as indicated by experimental evidence (Mascia et al, 2000) and by the conserved side chain positions of helix 2 (see 1OED and 2BG9), disulfide formation is possible only if the glycine receptor residue homologous to ␣ 1 Ala290 (␤ 2 Met286) is also accessible from the pocket inside the helical domain. Considering the uncertainty of model coordinates and the apparently significant flexibility of helix 3 (Akabas, 2004), a disulfide bridge crossing the intrasubunit pocket can easily be envisioned in models based on the twogap alignment.…”

Section: Discussionmentioning

confidence: 99%

“…Helix 3 of GABA A receptor ␣ 1 subunits has been point-mutated in 15 positions and probed with cysteine modifying reagents under the influence of various modulatory and GABA-mimetic drugs (Williams and Akabas, 2002;Akabas, 2004;Jung et al, 2005). Data indicate that the solvent accessibility of helix 3 residues changes differentially with different drugs (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Models of GABA_A Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Ernst

Brückner²,

Boresch³

et al. 2005

Mol Pharmacol

130

127

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Comparative models of the extracellular and transmembrane domains of GABA A receptors in the agonist-free state were generated based on the recently published structures of the nicotinic acetylcholine receptor. The models were validated by computational methods, and their reliability was estimated by analyzing conserved and variable elements of the cys-loop receptor topology. In addition, the methodological limits in the interpretation of such anion channel receptor models are discussed. Alignment ambiguities in the helical domain were resolved for helix 3 by placing two gaps into the linker connecting helices 2 and 3. The resulting models were shown to be consistent with a wide range of pharmacological and mutagenesis data from GABA A and glycine receptors. The loose packing of the models results in a large amount of solvent-accessible space and offers a natural explanation for the rich pharmacology and the great flexibility of these receptors that are known to exist in numerous drug-induced conformational states. Putative drug binding pockets found within and between subunits are described, and amino acid residues important for the action and subtype selectivity of volatile and intravenous anesthetics, barbiturates, and furosemide are shown to be part of these pockets. The entire helical domain, however, seems to be crucial not only for binding of drugs but also for transduction of binding to gating or of allosteric modulation. These models can now be used to design new experiments for clarification of pharmacological and structural questions as well as for investigating and visualizing drug induced conformational changes.GABA A receptors mediate a large part of the fast inhibitory transmission in the central nervous system and are the targets for many clinically important drugs, such as sedatives, hypnotics, anxiolytics, anticonvulsives, muscle relaxants, and anesthetics (Sieghart, 1995). They are composed of five subunits that can belong to different homologous subunit classes and form a chloride channel that can be opened by GABA. Individual neurons can express many different subunits, resulting in the formation of a large variety of functionally different receptor subtypes (Sieghart and Sperk, 2002). Depending on the subunit composition, these receptors exhibit a distinct pharmacology (Sieghart, 1995).The subunit organization with the extracellular ligand binding domain containing the "signature" disulfide, four transmembrane segments, and a large variable cytoplasmic domain (termed the "cytoplasmic loop") of unknown structure, as well as the receptor organization as a pentamer, are hallmarks of the superfamily of cys-loop receptors (pentameric ligand-gated ion channels) comprising the cation-conducting nicotinic acetylcholine (nACh) and serotonin type 3 (5HT 3 -) receptors and the anion-conducting GABA A and glycine receptors.In 2001, the X-ray crystallographic structure of acetylcholine binding protein (AChBP) has revealed the fold in which the ␤-strand rich "extracellular domain" of the superfam...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparative Models of GABA_A Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Ernst

Brückner²,

Boresch³

et al. 2005

Mol Pharmacol

130

127

View full text Add to dashboard Cite

show abstract

“…For more extensive discussion of the properties of GABA A receptors, readers are referred to other recent reviews (Akabas, 2004;Ernst et al, 2003;Luscher & Keller, 2004;Mody & Pearce, 2004;Rudolph & Mohler, 2004;Sieghart et al, 1999). GABA A receptors are pentameric heteromers and are members of the cys-loop family of ligand-gated ion channels.…”

Section: The Gaba a Receptormentioning

confidence: 99%

Mechanisms of neurosteroid interactions with GABAA receptors

Akk¹,

Covey²,

Evers³

et al. 2007

Pharmacology & Therapeutics

149

166

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Neuroactive steroids have some of their most potent actions by augmenting the function of GABA A receptors. Endogenous steroid actions on GABA A receptors may underlie important effects on mood and behavior. Exogenous neuroactive steroids have potential as anesthetics, anticonvulsants, and neuroprotectants. We have taken multiple approaches to understand more completely the interaction of neuroactive steroids with GABA A receptors. We have developed many novel steroid analogues in this effort. Recent work has resulted in synthesis of new enantiomer analogue pairs, novel ligands that probe various properties of the steroid pharmacophore, fluorescent neuroactive steroid analogues, and photoaffinity labels. Using these tools, combined with receptor binding and electrophysiological assays, we have begun to untangle the complexity of steroid actions at this important class of ligand-gated ion channel.

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“…Although a structural picture of pLGICs is rapidly emerging from the 4 Å resolution cryo-EM structure of the Torpedo nAChR (1), the crystal structures of the extracellular binding domain of the nAChR ␣-subunit (2) liganded and unliganded acetylcholine-binding proteins (AChBP), which are homologs of the extracellular binding domain (3,4), the crystal structures of full-length prokaryotic pLGIC homologs from Erwinia chrysanthemi (ELIC) and Gloeobacter violaceus (GLIC) (5-7), as well as the recent crystal structure of a related invertebrate pLGIC (8), our understanding of the structural elements and protein movements that couple neurotransmitter binding to channel gating is still under debate. For receptors in this superfamily, the neurotransmitter binding site is located in the extracellular N-terminal domain between adjacent subunits formed by at least six noncontiguous protein regions (loops A-F), whereas the channel gate is located 50 Å away in the trans-membrane region (9). Neurotransmitter binding is believed to trigger structural movements at the binding site that are propagated as a conformational wave to the channel gate (10).…”

mentioning

confidence: 99%

Structural Link between γ-Aminobutyric Acid Type A (GABAA) Receptor Agonist Binding Site and Inner β-Sheet Governs Channel Activation and Allosteric Drug Modulation

Venkatachalan

Czajkowski

2012

Journal of Biological Chemistry

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Background: Structural elements and protein movements underlying GABA A receptor activation are not completely resolved. Results: Glycine insertions in the extracellular ␤4-␤5 linker decrease GABA activation, invert antagonist efficacy, and reduce allosteric modulation. Conclusion: ␤4-␤5 linker is critical for mediating actions of GABA A receptor orthosteric and allosteric ligands. Significance: Detailed structural-functional understanding of GABA A receptor activation is key to understanding its modulation in diseased and healthy states.

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GABAA Receptor Structure–Function Studies: A Reexamination in Light of New Acetylcholine Receptor Structures

Cited by 46 publications

References 231 publications

Comparative Models of GABA_A Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Comparative Models of GABA_A Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Mechanisms of neurosteroid interactions with GABAA receptors

Structural Link between γ-Aminobutyric Acid Type A (GABAA) Receptor Agonist Binding Site and Inner β-Sheet Governs Channel Activation and Allosteric Drug Modulation

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GABAA Receptor Structure–Function Studies: A Reexamination in Light of New Acetylcholine Receptor Structures

Cited by 46 publications

References 231 publications

Comparative Models of GABAA Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Comparative Models of GABAA Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Mechanisms of neurosteroid interactions with GABAA receptors

Structural Link between γ-Aminobutyric Acid Type A (GABAA) Receptor Agonist Binding Site and Inner β-Sheet Governs Channel Activation and Allosteric Drug Modulation

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Product

Resources

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Comparative Models of GABA_A Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function

Comparative Models of GABA_A Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Function