Alternative transcripts of the GABAA receptor ε subunit in human and rat

Davies, Paul; McCartney, Melissa R.; Wang, W.; Hales, Tim G.; Kirkness, Ewen F.

doi:10.1016/s0028-3908(02)00153-3

Cited by 18 publications

(15 citation statements)

References 12 publications

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“…Similar overshoots were also present in previous studies of ⑀ subunit-containing receptors Neelands et al, 1999). Because ⑀ causes spontaneous channel opening that contributes to the baseline current (Neelands et al, 1999;Davies et al, 2001Davies et al, , 2002, the overshoot may result from a transient silencing of spontaneous openings, caused by GABA-induced desensitization.…”

Section: Resultssupporting

confidence: 82%

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

Wagner¹,

Goldschen-Ohm²,

Hales³

et al. 2005

J. Neurosci.

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GABA A receptors mediate synaptic and extrasynaptic inhibition. Native receptors consist of ␣ and ␤ subunits, which are required for function, and another "modulatory" subunit, for example, ␥, ␦, or ⑀. Of these, the ⑀ subunit has the most restricted distribution, confers resistance to neurosteroid and anesthetic modulation, and causes spontaneous channel opening. Little is known, however, about how ⑀ affects receptor kinetics, which in turn shape responses to both ambient and synaptic GABA exposure. Here, we expressed human ␣2␤1, ␣2␤1␥2, or ␣2␤1⑀ subunit combinations in human embryonic kidney 293 cells and used rapid solution exchange to study receptor kinetics in outside-out patches. The ⑀ subunit greatly slowed deactivation and recovery after brief GABA pulses. During long, saturating GABA pulses, the rate of desensitization was slower for ␣2␤1⑀ and ␣2␤1␥2 than for ␣2␤1. However, in ␣2␤1⑀, the final extent of desensitization was large compared with that of ␣2␤1␥2. Responses in ␣2␤1⑀, but not the others, were often followed by an "overshoot" above the baseline, suggesting that a fraction of channels are spontaneously open and are transiently silenced by receptor activation and subsequent desensitization. The baseline current and associated noise were reduced by picrotoxin, revealing that ⑀-containing channels are open ϳ4% of the time in the absence of GABA. These results suggest that, if ⑀-containing receptors are expressed at synapses, the synaptic currents would be long-lasting but may rundown quickly under high-frequency activation. In addition, silencing of spontaneous openings by desensitization raises the possibility that tonic inhibition mediated by ⑀-containing receptors may be regulated by phasic inhibition.

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Section: Resultssupporting

confidence: 82%

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

Wagner¹,

Goldschen-Ohm²,

Hales³

et al. 2005

J. Neurosci.

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“…During heterologous expression, this subunit has been shown to confer several properties to the GABA A Rs: Whiting et al (1997) reported a higher rate of desensitization of maximal GABA responses in oocytes and human embryonic kidney HEK 293 cells, whereas Neelands et al (1999) did not detect fast desensitization but described constitutive activity of ⑀-containing GABA A Rs. The same spontaneous activity was reported by another group (Davies et al, 2002). Controversial data were obtained by different groups regarding GABA A R modulation by anesthetics, most probably attributable to the different expression levels of the ⑀-subunit in different artificial systems (Thompson et al, 2002): Davies et al (1997Davies et al ( , 2002 found ⑀-containing GABA A Rs resistant to anesthetics; Thompson et al (1998) did not.…”

Section: Introductionsupporting

confidence: 72%

“…The same spontaneous activity was reported by another group (Davies et al, 2002). Controversial data were obtained by different groups regarding GABA A R modulation by anesthetics, most probably attributable to the different expression levels of the ⑀-subunit in different artificial systems (Thompson et al, 2002): Davies et al (1997Davies et al ( , 2002 found ⑀-containing GABA A Rs resistant to anesthetics; Thompson et al (1998) did not. In an elegant study by Irnaten et al (2002), cardiac parasympathetic neurons were transfected with the ⑀-subunit, which changed the pentobarbital modulation of spontaneous IPSCs (sIPSCs) recorded from these cells: the decay time constants ( dec ) of IPSCs, normally prolonged by anesthetic, were unaffected after transfection.…”

Section: Introductionsupporting

confidence: 72%

“…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%

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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). We tested rat ␣1␤3 receptors to determine whether the rodent subunit (Davies et al, 2002) also conferred furosemide-sensitive tonic currents. Picrotoxin (100 M) applied to the bath inhibited relatively large spontaneous currents mediated by ␣1␤3 receptors expressed in HEK293 cells (Fig.…”

Section: Gaba-independent Tonic Currents 543mentioning

confidence: 99%

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

McCartney

Deeb²,

Henderson³

et al. 2007

Molecular Pharmacology

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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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Alternative transcripts of the GABAA receptor ε subunit in human and rat

Cited by 18 publications

References 12 publications

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

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

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

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Alternative transcripts of the GABAA receptor ε subunit in human and rat

Cited by 18 publications

References 12 publications

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABAAReceptor

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABAAReceptor

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

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Product

Resources

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Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

Kinetics and Spontaneous Open Probability Conferred by the ϵ Subunit of the GABA_AReceptor

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