Neurosteroid modulation of recombinant rat α5β2γ2L and α1β2γ2L GABAA receptors in Xenopus oocyte

Rahman, Mozibur; Lindblad, Charlotte; Johansson, Ingvar; Bäckström, Torbjörn; Wang, Mingde

doi:10.1016/j.ejphar.2006.07.039

Cited by 28 publications

(19 citation statements)

References 28 publications

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“…Behavioral responses also show subunit isoform specificity, with ␣ 1 mediating sedative effects (20), ␣ 2/3 mediating anxiolytic effects (4), and ␣ 5 mediating effects on memory (3). The impact of ␣-subunit isoforms also seems to influence the responsiveness of GABA A receptors to neurosteroid-mediated allosteric potentiation, with ␣ 1 and ␣ 3 demonstrating a heightened responsiveness to this steroid class (19).…”

Section: Discussionmentioning

confidence: 99%

Targeting the restricted α-subunit repertoire of airway smooth muscle GABA_A receptors augments airway smooth muscle relaxation

Gallos

Yim

Chang

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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The prevalence of asthma has taken on pandemic proportions. Since this disease predisposes patients to severe acute airway constriction, novel mechanisms capable of promoting airway smooth muscle relaxation would be clinically valuable. We have recently demonstrated that activation of endogenous airway smooth muscle GABAA receptors potentiates ␤-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the ␣-subunit component of these GABAA receptors is limited to the ␣4-and ␣5-subunits. We questioned whether ligands with selective affinity for these GABAA receptors could promote relaxation of airway smooth muscle. RT-PCR analysis of GABAA receptor subunits was performed on RNA isolated by laser capture microdissection from human and guinea pig airway smooth muscle. Membrane potential and chloride-mediated current were measured in response to GABAA subunit-selective agonists in cultured human airway smooth muscle cells. Functional relaxation of precontracted guinea pig tracheal rings was assessed in the absence and presence of the ␣4-subunit-selective GABAA receptor agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the ␣4-and ␣5-GABAA receptor subunits was identified in RNA isolated by laser capture dissection from guinea pig and human airway smooth muscle tissues. Activation of airway smooth muscle GABAA receptors with agonists selective for these subunits resulted in appropriate membrane potential changes and chloride currents and promoted relaxation of airway smooth muscle. In conclusion, selective subunit targeting of endogenous airway smooth muscle-specific GABAA receptors may represent a novel therapeutic option for patients in severe bronchospasm.

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Section: Discussionmentioning

confidence: 99%

Targeting the restricted α-subunit repertoire of airway smooth muscle GABA_A receptors augments airway smooth muscle relaxation

Gallos

Yim

Chang

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…5α-steroid, but not 5β-steroids, showed a high degree of enantioselectivity/enantiospecificity in their action as modulator of the GABA A -receptor and as anesthetics (Covey et al, 2000). The efficacy of 3β5β-P to inhibit GABA A -receptor is significantly different from 3β5α-P (Rahman et al, 2006; Wang et al, 2007). 5β-reduced antagonist neurosteroids cause significant higher inhibition than the 5α-isomers.…”

Section: The Effect Of Neurosteroids On the Gabaa-receptormentioning

confidence: 99%

Neurosteroids and GABA-A Receptor Function

Wang¹

2011

Front. Endocrin.

138

106

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Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α, 17α-diol (Adiol), and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) enhance the GABA-mediated Cl- currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABAA-receptor function and activate δ-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnane steroids and pregnenolone sulfate (PS) are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions.

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“…With respect to α subunit composition, α 6 -containing recombinant receptors show the greatest sensitivity to modulation by positive neurosteroids, and those containing α 1 or α 3 subunits are slightly more sensitive than those containing α 2 or α 4 (for review Belelli et al, 2002). Published reports diverge with respect to the sensitivity of α 5 -containing receptors to positive neurosteroids (Belelli et al, 2002;Rahman et al, 2006). Neither the α 4 nor the α 6 subunit is expressed in hypothalamic/basal forebrain regions that regulate reproductive control, and studies addressing the relevance of α subunit composition with respect to positive neurosteroid modulation of reproductive behaviors have focused on α 1 versus α 2 expression, which changes with hormonal state (see Section 7).…”

Section: Neurosteroidsmentioning

confidence: 99%

“…A recent report by Rahman et al (2006) indicates that substitution of an α 5 for an α 1 subunit in recombinant α x β 2 γ 2L receptors results in enhanced efficacy, but no effect on potency, for a panel of inhibitory modulators including pregnenolone sulfate, DHEAS, and a number of 3β-hydroxypregnane steroids. In contrast to the positive neurosteroids, substitution of a δ for the γ 2 subunit in α 4 β 3 x recombinant receptors has no effect on the inhibitory modulation elicited by pregnenolone sulfate (Brown et al, 2002).…”

Section: Neurosteroidsmentioning

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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Neurosteroid modulation of recombinant rat α5β2γ2L and α1β2γ2L GABAA receptors in Xenopus oocyte

Cited by 28 publications

References 28 publications

Targeting the restricted α-subunit repertoire of airway smooth muscle GABA_A receptors augments airway smooth muscle relaxation

Targeting the restricted α-subunit repertoire of airway smooth muscle GABA_A receptors augments airway smooth muscle relaxation

Neurosteroids and GABA-A Receptor Function

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

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Neurosteroid modulation of recombinant rat α5β2γ2L and α1β2γ2L GABAA receptors in Xenopus oocyte

Cited by 28 publications

References 28 publications

Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation

Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation

Neurosteroids and GABA-A Receptor Function

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

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Targeting the restricted α-subunit repertoire of airway smooth muscle GABA_A receptors augments airway smooth muscle relaxation

Targeting the restricted α-subunit repertoire of airway smooth muscle GABA_A receptors augments airway smooth muscle relaxation