The pharmacology of spontaneously open α1β3ε GABAA receptor–ionophores

Maksay, Gábor; Thompson, Sally A.; Wafford, Keith A.

doi:10.1016/s0028-3908(03)00116-3

Cited by 42 publications

(35 citation statements)

References 32 publications

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“…The shift of baseline current by GABA A R antagonists in our study represented no more than 1% of the maximal GABA-mediated currents and was not observed in all ⑀-positive cells; in contrast, some ⑀-negative cells demonstrated spontaneous activity sensitive to GABA A R antagonists. For comparison, in HEK 293 cells transfected with the rat ⑀-subunit, such currents represented 83% of the maximal GABAmediated currents (Davies et al, 2002) and 38% in oocytes transfected with the human ⑀-subunit (Maksay et al, 2003). It is therefore likely that the high constitutive activity of heterologously expressed ⑀-subunits occurs only in artificially constructed receptors.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Sergeeva¹,

Andreeva²,

Garret³

et al. 2005

J. Neurosci.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Sergeeva¹,

Andreeva²,

Garret³

et al. 2005

J. Neurosci.

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“…1F). Furosemide inhibits currents mediated by spontaneously gating recombinant GABA A receptors containing the human subunit (Maksay et al, 2003) but had no effect on tonic currents recorded from pyramidal neurons (Fig. 1F).…”

Section: Gaba-independent Tonic Currents 541mentioning

confidence: 97%

Tonically Active GABA_A Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating

McCartney

Deeb²,

Henderson³

et al. 2006

Mol Pharmacol

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Phasic and tonic inhibitory currents of hippocampal pyramidal neurons exhibit distinct pharmacological properties. Picrotoxin and bicuculline methiodide inhibited both components, consistent with a role for GABA A receptors; however, gabazine, at a concentration that abolished miniature GABAergic inhibitory postsynaptic currents and responses to exogenous GABA, had no effect on tonic currents. Because all GABA-activated GABA A receptors in pyramidal neurons are gabazine-sensitive, it follows that tonic currents are not GABA-activated. Furthermore, picrotoxin-sensitive spontaneous single-channel events recorded from outside-out patches had the same chord conductance as GABA-activated channels and were gabazineresistant. Therefore, we hypothesize that GABA A receptors, constitutively active in the absence of GABA, mediate tonic current; the failure of gabazine to block tonic current reflects a lack of negative intrinsic efficacy of the antagonist. We compared the negative efficacies of bicuculline and gabazine using the general anesthetic propofol to directly activate GABA A receptors native to pyramidal neurons or ␣1␤3␥2 receptors recombinantly expressed in human embryonic kidney 293 cells. Propofol activated gabazine-resistant, bicuculline-sensitive currents when applied to either preparation. Although gabazine had negligible efficacy as an inhibitor of propofol-activated currents, it prevented inhibition by bicuculline, which acts as an inverse agonist inhibiting GABA-independent gating. Recombinant ␣1␤1/3␥2 receptors also mediated agonist-independent tonic currents that were resistant to gabazine and inhibited by bicuculline. Thus, gabazine is a competitive antagonist with negligible negative efficacy and is therefore unable to inhibit GABA A receptors that are active in the absence of GABA because of either anesthetic or spontaneous gating. Moreover, spontaneously active GABA A receptors mediate gabazine-resistant tonic currents in pyramidal neurons.

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“…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). Both pregnenolone sulfate and DHEAS inhibit spontaneous currents through α 1 β 3 ε recombinant receptors, but the sensitivity of these receptors to the negative modulators is low, with IC 50 = 10.1 μM and 3.9 μM for DHEAS and pregnenolone sulfate, respectively (Maksay et al, 2003).…”

Section: Neurosteroidsmentioning

confidence: 97%

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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The pharmacology of spontaneously open α1β3ε GABAA receptor–ionophores

Cited by 42 publications

References 32 publications

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Tonically Active GABA_A Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating

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

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The pharmacology of spontaneously open α1β3ε GABAA receptor–ionophores

Cited by 42 publications

References 32 publications

Pharmacological Properties of GABAAReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Pharmacological Properties of GABAAReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Tonically Active GABAA Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating

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

Contact Info

Product

Resources

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Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Pharmacological Properties of GABA_AReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

Tonically Active GABA_A Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating