Subunit dependent modulation of GABAA receptor function by neuroactive steroids

Maitra, Rajatavo; Reynolds, James N.

doi:10.1016/s0006-8993(98)01316-x

Cited by 71 publications

(42 citation statements)

References 38 publications

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“…4B), suggesting that the region from TM4 to the C-terminus of the GABA A receptor a subunit may not be sufficient for the action of allopregnanolone. This is consistent with the evidence that alphaxalone, a neurosteroid anesthetic, may act on GABA A receptors via the N-terminal side of TM2 of the a subunit [15] or a residue located in TM1 of the b subunit [23], since alphaxalone is a synthetic analog of allopregnanolone and has similar efficacy at GABA A receptors [24]. Moreover, as demonstrated in the present study (Fig.…”

Section: The Action Of 5a-thdoc and Allopregnanolone On C9supporting

confidence: 93%

Sites of positive allosteric modulation by neurosteroids on ionotropic $gamma;-aminobutyric acid receptor subunits

UENO¹

2004

FEBS Letters

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Neurosteroids are known as allosteric modulators of ionotropic c-aminobutyric acid (GABA) receptors. Here, we investigated sites of positive allosteric modulation by allotetrahydrodeoxycorticosterone (5a-THDOC) at GABA receptors using the technique of chimeragenesis and the Xenopus oocyte expression system. Our findings have demonstrated that the region from transmembrane segment (TM) 4 to the C-terminus of the GABA A receptor a1 subunit is crucial for the action of 5a-THDOC, but insufficient for the action of another neurosteroid allopregnanolone, suggesting that a specific region critical for neurosteroid action at GABA receptors exists in the domain between TM4 and the C-terminus of GABA receptor subunits.

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Section: The Action Of 5a-thdoc and Allopregnanolone On C9supporting

confidence: 93%

Sites of positive allosteric modulation by neurosteroids on ionotropic $gamma;-aminobutyric acid receptor subunits

UENO¹

2004

FEBS Letters

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“…Receptors containing a ␥1 or a ␥3 subunit produced an intermediate profile with low concentrations of tracazolate potentiating to a small degree the GABA EC 20 , whereas higher concentrations caused inhibition. These differing functional effects are in contrast to the general anesthetic agents such as pentobarbitone and propofol and the neuroactive steroids, which potentiate all the receptor subtypes examined herein Thompson et al, 1998;Maitra and Reynolds, 1999). In addition, these agents are also dissimilar to tracazolate because they do not display ␤ subunit selectivity.…”

Section: Discussionmentioning

confidence: 91%

Tracazolate Reveals a Novel Type of Allosteric Interaction with Recombinant γ-Aminobutyric Acid_A Receptors

et al. 2002

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Tracazolate, a pyrazolopyridine, is an anxiolytic known to interact with ␥-aminobutyric acid (GABA) A receptors, adenosine receptors, and phosphodiesterases. Its anxiolytic effect is thought to be via its interaction with GABA A receptors. We now report the first detailed pharmacological study examining the effects of tracazolate on a range of recombinant GABA A receptors expressed in Xenopus laevis oocytes. Replacement of the ␥2s subunit within the ␣1␤3␥2s receptor with the ⑀ subunit caused a dramatic change in the functional response to tracazolate from potentiation to inhibition. The ␥2s subunit was not critical for potentiation because ␣1␤3 receptors were also potentiated by tracazolate. ␥2/⑀ chimeras revealed a critical Nterminal domain between amino acids 206 and 230 of ␥2, governing the nature of this response. Replacement of the ␤3 subunit with the ␤1 subunit within ␣1␤3␥2s and ␣1␤3⑀ receptors also revealed selectivity of tracazolate for ␤3-containing receptors, determined by asparagine at position 265 within transmembrane 2. Replacement of ␥2s with ␥1 or ␥3 revealed a profile intermediate to that of ␣1␤1⑀ and ␣1␤1␥2s. ␣1␤1␦ receptors were also potentiated by tracazolate; however, the maximum potentiation of the EC 20 was much greater than on ␣1␤1␥2. Concentration-response curves to GABA in the presence of tracazolate for ␣1␤1⑀ and ␣1␤1␥2s revealed a concentration-related decrease in maximum current amplitude, but a leftward shift in the EC 50 only on ␣1␤1␥2. Like ␣1␤1␥2s, GABA concentration-response curves on ␣1␤1␦ receptors were shifted to the left with increased maximum responses. Tracazolate has a unique pharmacological profile on recombinant GABA A receptors: its potency (EC 50 ) is influenced by the nature of the ␤ subunit; but more importantly, its intrinsic efficacy, potentiation, or inhibition is determined by the nature of the third subunit (␥1-3, ␦, or ⑀) within the receptor complex.

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“…The γ subunit, particularly the γ 2 isoforms, is important for alcohol effects. In contrast, allopregnanolone increases Cl -flux in multiple recombinant GABA A receptor complexes, suggesting that the modulatory site is located within the transmembrane portion of the receptor complex (Puia et al 1992;Belleli et al 1999;Maitra and Reynolds 1999). Additionally, the effect of alcohol on aggression in squirrel monkeys and in rats can be blocked by treatment with the ben-480 Fig.…”

Section: Discussionmentioning

confidence: 99%

Alcohol, allopregnanolone and aggression in mice

et al. 2000

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Subunit dependent modulation of GABAA receptor function by neuroactive steroids

Cited by 71 publications

References 38 publications

Sites of positive allosteric modulation by neurosteroids on ionotropic $gamma;-aminobutyric acid receptor subunits

Sites of positive allosteric modulation by neurosteroids on ionotropic $gamma;-aminobutyric acid receptor subunits

Tracazolate Reveals a Novel Type of Allosteric Interaction with Recombinant γ-Aminobutyric Acid_A Receptors

Alcohol, allopregnanolone and aggression in mice

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Subunit dependent modulation of GABAA receptor function by neuroactive steroids

Cited by 71 publications

References 38 publications

Sites of positive allosteric modulation by neurosteroids on ionotropic $gamma;-aminobutyric acid receptor subunits

Sites of positive allosteric modulation by neurosteroids on ionotropic $gamma;-aminobutyric acid receptor subunits

Tracazolate Reveals a Novel Type of Allosteric Interaction with Recombinant γ-Aminobutyric AcidA Receptors

Alcohol, allopregnanolone and aggression in mice

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Tracazolate Reveals a Novel Type of Allosteric Interaction with Recombinant γ-Aminobutyric Acid_A Receptors