Structure, Pharmacology, and Function of GABAA Receptor Subtypes

Sieghart, Werner

doi:10.1016/s1054-3589(06)54010-4

Cited by 499 publications

(598 citation statements)

References 141 publications

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“…Representative agents that have been identified as increasing the activity of this inhibitory receptor include propofol, etomidate, benzodiazepines, barbiturates, isoflurane, sevoflurane, and neurosteroids. 114,118,138,139 GABA A receptor-mediated inhibition occurs in two types: phasic inhibition, which is mediated by activation of postsynaptic GABA A receptors after synchronous release of presynaptic neurotransmitters, and tonic inhibition, which is generated by high-affinity slowly desensitizing extrasynaptic GABA A receptors that are activated by low ambient concentrations of GABA. 140 Phasic inhibition maintains high-fidelity neuronal communication and produces precise timing of action potentials and synchronization of neuronal populations.…”

Section: General Anesthetics and The Neural Substrates Of Memorymentioning

confidence: 99%

Inhibition of learning and memory by general anesthetics

Wang

Orser

2010

Can J Anesth/J Can Anesth

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Section: General Anesthetics and The Neural Substrates Of Memorymentioning

confidence: 99%

Inhibition of learning and memory by general anesthetics

Wang

Orser

2010

Can J Anesth/J Can Anesth

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“…Subunit composition is regulated with age and development, in a region-specific manner and in response to exposure to both exogenous and endogenous substances. Subunit composition, in turn, determines not only basic biophysical properties of the receptor, but also the sensitivity of this protein to a host of psychoactive compounds whose predominant mechanism of actions is allosteric modulation of channel function (for review, Sieghart, 1995). As a general rule, the hypothalamus/basal forebrain does not undergo the characteristic postnatal shift during which there is a significant up-regulation of the α 1 subunit and concomitant down-regulation of the α 2/3 subunits (Fritschy et al, 1994).…”

Section: Subunit Expression In the Hypothalamus/basal Forebrainmentioning

confidence: 99%

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through nongenomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

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“…GABA (g-amino-butyric acid) is the primary inhibitory neurotransmitter in brain (Mody et al, 1994;Sieghart, 1995). Evidence accumulated over several decades suggested that ethanol influences GABA function (Allan and Harris, 1987;Frye and Breese, 1982;Liljequist and Engel, 1982;Martz et al, 1983;Mereu and Gessa, 1985;Nestoros, 1980;Simson et al, 1991;see Crews et al, 1996).…”

Section: Interaction Of Ethanol With the Gaba System In Vivomentioning

confidence: 99%

“…The GABA A receptor is assembled as a heteropentamere (Macdonald and Olsen, 1994;Hevers and Lüddens, 1998) from a collection of differing receptor subunitsFsix a, three b, three g, three r, and d, x, p, and y subunits (Benke et al, 1991b;Lüddens, 1998, 2002;Khan et al, 1994;Korpi et al, 2002;Lüddens and Korpi, 1995;McKernan and Whiting, 1996;Rudolph et al, 2001;Sieghart, 1995;Wisden et al, 1992). The distribution of these differing assortments of receptor subunits was found to be heterogeneous, allowing for diversity of GABA A receptor complexes Mckernan and Whiting, 1996;Rudolph et al, 2001;Wisden et al, 1992).…”

Section: Hypothesis For Ethanol Action On a Type-1-bzd Receptormentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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Structure, Pharmacology, and Function of GABAA Receptor Subtypes

Cited by 499 publications

References 141 publications

Inhibition of learning and memory by general anesthetics

Inhibition of learning and memory by general anesthetics

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

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