Mechanism of α-subunit selectivity of benzodiazepine pharmacology at γ-aminobutyric acid type A receptors

Wingrove, Peter B.; Safo, Patrick; Wheat, Lola; Thompson, Sally A.; Wafford, Keith A.; Whiting, Paul

doi:10.1016/s0014-2999(02)01279-7

Cited by 37 publications

(24 citation statements)

References 29 publications

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“…Unlike synaptic GABA A -Rs, extrasynaptic GABA A -Rs are insensitive to both hypnotics. These data are in agreement with previous reports that GABA A -Rs that contain ␣1 subunits have a high affinity for zolpidem and that there is no BZ site in GABA A -Rs that contain ␣4 subunits (Knoflach et al, 1996;Whittemore et al, 1996;Wingrove et al, 2002). Our results also suggest that eszopiclone has a greater efficacy at ␣3␤3␥2 than at ␣1␤2␥2 GABA A -Rs (see Fig.…”

Section: Discussionsupporting

confidence: 94%

“…Zolpidem is known for its relative specificity for receptors containing GABA A -R ␣1 subunits (Pritchett and Seeburg, 1990;Wingrove et al, 2002), and this would be consistent with our finding that IPSCs from VB neurons are more sensitive to zolpidem than those from RTN neurons. GABA A -R ␣1 subunits have been suggested as the primary site of action for the sedative effects of all drugs acting through BZ sites because in behavioral studies of the ␣1 knockin (H101R) mouse, the sedative action of diazepam was reduced or abolished (Rudolph and Möhler, 2004).…”

Section: Discussionsupporting

confidence: 90%

“…Two types of BZ binding sites were proposed in the 1980s, and we now know that GABA A -Rs with BZ 1 sites contain ␣1 subunits, whereas those with BZ 2 sites contain ␣2, ␣3, or ␣5 subunits. Zolpidem has a selective high affinity for BZ 1 sites and a very low affinity and extremely low efficacy at receptors that contain ␣5 subunits (Pritchett and Seeburg, 1990;Wingrove et al, 2002), whereas the subunit specificity of eszopiclone has not yet been fully described.…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian GABA A receptors in the central nervous system are pentameric structures consisting of distinct subunits, which can include ␣ 1-6 , ␤ 1-3 , and ␥ 1-3 or ␦ (Sieghart and Sperk, 2002). Zolpidem is highly selective for ␣ 1 ␤ x ␥ 2 GABA A -Rs (Pritchett and Seeburg, 1990;Wingrove et al, 2002), which have been implicated in the hypnotic actions of the BZs (Rudolph and Möhler, 2004). The selectivity of eszopiclone is not yet fully understood, although the drug has also been shown to act at ␥ 2 -containing GABA A -Rs, including ␣ 1 ␤ x ␥ 2 .…”

mentioning

confidence: 99%

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The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

Fan¹,

Goldstein²,

Harrison³

2008

J Pharmacol Exp Ther

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Eszopiclone (Lunesta; Sepracor, Marlborough, MA) and zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)-imidazo(1,2-a)pyridine-3-acetamide] are among the most commonly prescribed hypnotics in use in the United States. The thalamus plays a pivotal role in sleep regulation and rhythmicity. Two distinct subtypes of synaptic GABA A receptors (GABA A -Rs), ␣ 1 ␤ 2 ␥ 2 and ␣ 3 ␤ 3 ␥ 2 , are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABA A -Rs composed of ␣ 4 ␤ 2 ␦ subunits. In this study, we compared the effects of eszopiclone and zolpidem on miniature inhibitory postsynaptic currents (IPSCs), spontaneous IPSCs, and tonic inhibition in the mouse thalamus. Eszopiclone (0.1-1 M) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at Ն0.3 M. IPSCs of RTN neurons were more sensitive to eszopiclone than zolpidem at all concentrations tested. On the other hand, IPSCs of relay neurons in the ventrobasal nucleus (VB) were more sensitive to zolpidem than eszopiclone. Zolpidem (0.1-1 M) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at Ն0.3 M. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABA A -Rs of RTN neurons than in relay neurons, whereas zolpidem exerts bigger effects on relay neurons than RTN neurons. This distinct pattern of activity on thalamic neurons may contribute to some of the observed differences in the clinical effects of these two hypnotics.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

Fan¹,

Goldstein²,

Harrison³

2008

J Pharmacol Exp Ther

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“…The majority of GABA A Rs are composed of two a subunits, two b subunits, and a single g subunit (Pritchett and Seeburg, 1991;Chang et al, 1996;Graham et al, 1996;Tretter et al, 1997;Wingrove et al, 2002), with the GABA binding site located on the a/b subunit (Casalotti et al, 1986). Residues that contribute to the GABA binding site are F64 on the a subunit and Y157, T160, and Y205 located on the b subunit (Amin and Weiss, 1993;Amin et al, 1997;Baur and Sigel, 2003).…”

Section: Neural Systems and The Neurochemical Basis Of Anxietymentioning

confidence: 99%

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

Farb

Ratner

2014

Pharmacol Rev

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Pharmacology of the GABA_AReceptor

Berezhnoy

Gravielle

Farb

2007

Handbook of Contemporary Neuropharmacology

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GABA mediates most inhibitory synaptic transmission in the adult vertebrate CNS by activating type‐A GABA receptors that contain an integral ion channel and type‐B GABA receptors that are G‐protein coupled. GABA A receptors have been a rich target for the development of therapeutics for treatment of anxiety disorders, convulsive disorders, sleep disturbances, and for the induction of anesthesia. GABA A receptors are composed of five membrane‐spanning subunits, selected from eight subunit subtypes (α, β, γ, δ, η, ρ, π, and θ) many of which contain multiple isoforms yielding at least 21 distinct subunit variants. These variations in subunit composition can have profound effects upon the functionality, pharmacology, and subcellular distribution of receptor subtypes. This chapter focuses on the relationship between receptor architecture and pharmacology of a large number of clinically relevant compounds such as benzodiazepines, barbiturates, anesthetics, neurosteroids and alcohols.

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Mechanism of α-subunit selectivity of benzodiazepine pharmacology at γ-aminobutyric acid type A receptors

Cited by 37 publications

References 29 publications

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

Pharmacology of the GABA_AReceptor

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Mechanism of α-subunit selectivity of benzodiazepine pharmacology at γ-aminobutyric acid type A receptors

Cited by 37 publications

References 29 publications

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

Pharmacology of the GABAAReceptor

Contact Info

Product

Resources

About

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

Pharmacology of the GABA_AReceptor