Benzodiazepines Modulate GABA<sub>A</sub>Receptors by Regulating the Preactivation Step after GABA Binding

Gielen, Marc; Lumb, M.; Smart, Trevor G.

doi:10.1523/jneurosci.5663-11.2012

Cited by 102 publications

(98 citation statements)

References 32 publications

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“…The equilibrium constant describing the transition between these two shut states was denoted as ⌽ and it is intriguing that macropatch and single channel analysis failed to detect any kinetic parameter that could be attributed to the ␥ subunit isoform other than ⌽. This constant was Ͻ1 only if the receptor expressed the ␥1 isoform and may pertain to GABA A R modulation by benzodiazepines, which a recent study has shown to manifest as an enhancement of ⌽ in ␥2-containing GABA A Rs (47). Our data are consistent with the notion that ⌽ is ␥ isoform dependent, the lower value of ⌽ for ␥1-containing receptors might suggest a reduced capacity for enhancement by benzodiazepine modulators.…”

Section: Discussionsupporting

confidence: 89%

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

Dixon

Sah

Lynch³

et al. 2014

Journal of Biological Chemistry

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Background: GABA A R ␣2 and ␥1 subunits are highly expressed in amygdala but their influence on synaptic currents is unknown. Results: ␣2 subunits increased GABA affinity thereby slowing current deactivation; ␥1 subunits reduced synaptic receptor clustering. Conclusion: These subunits may differentially shape synaptic kinetics. Significance: Understanding how ␣2 and ␥1 subunits shape synaptic currents may help us understand amygdala processing mechanisms.

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Section: Discussionsupporting

confidence: 89%

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

Dixon

Sah

Lynch³

et al. 2014

Journal of Biological Chemistry

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“…In agreement with previous studies (Campo-Soria et al, 2006;Gielen et al, 2012), the maximal current amplitude evoked by GABA through a 1 b 2 g 2S in the presence of a saturating diazepam concentration (3 mM) (R max 6 S.E.M. = 110 6 10%; n 5 4) did not differ significantly from that elicited by GABA alone, whereas the benzodiazepine gave rise to a small but significant (2.4-fold) left shift of the concentrationresponse curve [EC 50 (pEC 50 6 S.E.M.)…”

Section: Functional Characterization Of Methaqualone At Human Gaba a supporting

confidence: 93%

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Hammer¹,

Bader²,

Ehnert³

et al. 2015

Mol Pharmacol

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In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human a 1,2,3,5 b 2,3 g 2S GABA A receptors (GABA A Rs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the a 4,6 b 1,2,3 d GABA A R subtypes, ranging from inactivity (Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABA A R. Instead, the compound is proposed to act through the transmembrane b(1) /a (-) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABA A R modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 mM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABA A Rs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABA A Rs give rise to its effects as a therapeutic and recreational drug.

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“…The different numbers of binding sites required for the action of each ligand indicates divergent mechanisms. Benzodiazepines potentiate agonist responses by modulating activation or preactivation steps (33), whereas agonists themselves are intimately involved in activation. PNU, in contrast, potentiates agonist-induced responses by slowing α7 desensitization (14,15,34).…”

Section: Discussionmentioning

confidence: 99%

Stoichiometry for drug potentiation of a pentameric ion channel

daCosta¹,

Sine

2013

Proc. Natl. Acad. Sci. U.S.A.

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Drug modulation of ion channels is a powerful means to alter physiological responses for therapeutic benefit, yet the structural bases of modulation remain poorly understood. Here we study potentiation of nicotinic α7 acetylcholine receptors, which are emerging drug targets in several neurological disorders. α7 receptors are ligand-gated ion channels composed of five identical subunits, each bearing a site for the potentiating drug PNU-120596 (PNU). How the individual subunits contribute to PNU potentiation is not known. Taking advantage of a PNU-resistant mutant, we generated receptors composed of normal and PNU-resistant subunits and tagged one of the subunits with conductance mutations to report subunit stoichiometry. We then used patch clamp recording to monitor PNU potentiation of single α7 receptors with defined stoichiometry in real time. We find that potentiation depends steeply on the number of PNU-resistant subunits and that four, and possibly five, subunits must be sensitive to PNU for potentiation to occur. Thus, by monitoring the activity of every possible subunit combination, our findings predict that at the macroscopic level, PNU potentiation is highly cooperative.

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Benzodiazepines Modulate GABA_AReceptors by Regulating the Preactivation Step after GABA Binding

Cited by 102 publications

References 32 publications

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Stoichiometry for drug potentiation of a pentameric ion channel

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Benzodiazepines Modulate GABAAReceptors by Regulating the Preactivation Step after GABA Binding

Cited by 102 publications

References 32 publications

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

A Multifaceted GABAAReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Stoichiometry for drug potentiation of a pentameric ion channel

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Product

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Benzodiazepines Modulate GABA_AReceptors by Regulating the Preactivation Step after GABA Binding

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)