The neuroactive steroids alphaxalone and pregnanolone increase the conductance of single GABAA channels in newborn rat hippocampal neurons

Gaul, Simon; Ozsarac, Nesrin; Liu, Lu; Fink, Rainer H. A.; Gage, Peter W.

doi:10.1016/j.jsbmb.2006.09.042

Cited by 10 publications

(7 citation statements)

References 36 publications

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“…An altered open channel conformation is also consistent with differences in rates of desensitization that have been observed with whole-cell responses in these two situations (Gill et al, 2011(Gill et al, , 2012. These findings are also consistent with a report suggesting that allosteric modulators can increase the single-channel conductance of GABA A receptors (Gaul et al, 2007).…”

supporting

confidence: 90%

Activation of α7 Nicotinic Receptors by Orthosteric and Allosteric Agonists: Influence on Single-Channel Kinetics and Conductance

et al. 2012

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Nicotinic acetylcholine receptors (nAChRs) are oligomeric transmembrane proteins in which five subunits coassemble to form a central ion channel pore. Conventional agonists, such as acetylcholine (ACh), bind to an orthosteric site, located at subunit interfaces in the extracellular domain. More recently, it has been demonstrated that nAChRs can also be activated by ligands binding to an allosteric transmembrane site. In the case of ␣7 nAChRs, ACh causes rapid activation and almost complete desensitization. In contrast, allosteric agonists such as 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quin oline-8-sulfonamide (4BP-TQS) activate ␣7 nAChRs more slowly and cause only low levels of apparent desensitization. In the present study, single-channel patch-clamp recording has been used to investigate differences in the mechanism of activation of ␣7 nAChRs by ACh and 4BP-TQS. The most striking difference between activation by ACh and 4BP-TQS is in single-channel kinetics. In comparison with activation by ACh, single-channel open times and burst lengths are substantially longer (ϳ160 -800-fold, respectively), and shut times are shorter (ϳ8-fold) when activated by 4BP-TQS. In addition, coapplication of ACh and 4BP-TQS results in a further increase in single-channel burst lengths. Mean burst lengths seen when the two agonists are coapplied (3099 Ϯ 754 ms) are ϳ2.5-fold longer than with 4BP-TQS alone and ϳ370-fold longer than with ACh alone. Intriguingly, the main single-channel conductance of ␣7 nAChRs, was significantly larger when activated by 4BP-TQS (100.3 Ϯ 2.4 pS) than when activated by ACh (90.0 Ϯ 2.7 pS), providing evidence that activation by allosteric and orthosteric agonists results in different ␣7 nAChRs openchannel conformations.

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confidence: 90%

Activation of α7 Nicotinic Receptors by Orthosteric and Allosteric Agonists: Influence on Single-Channel Kinetics and Conductance

et al. 2012

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“…The increases in conductance were seen predominantly in cell-attached patches onto neurons expressing native receptors, but were also observed in outside-out patches. They found similar increases in channel conductance induced by pentobarbital, 71 neuroactive steroids, 72 propofol, 73 and GABA itself. 74 The same group 75 subsequently found that high conductance (>40 pS) GABA A R channels were not observed in recombinant α1-β1-γ2 GABA A Rs expressed in L929 cells, nor was conductance increased by diazepam unless the GABA A R-associated protein (GABARAP) was also co-expressed, apparently facilitating clustering of GABA A R proteins through its interaction with the cytoplasmic loop of the γ2 subunit as occurs at synapses with native receptors.…”

Section: Benzodiazepinesmentioning

confidence: 80%

Molecular mechanisms of antiseizure drug activity at GABAA receptors

Greenfield

2013

Seizure

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The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, led to the development of ganaxolone. Other agents modulate GABAergic “tone” by regulating the synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane chloride gradient, which changes during development and in chronic epilepsy. This may provide an additional target for “GABAergic” ASDs. GABAAR subunit changes occur both acutely during status epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. Manipulation of subunit expression patterns or novel ASDs targeting the altered receptors may provide a novel approach for seizure prevention.

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“…reduced anxiety. At the molecular level, individual GABA A ion-channel responses to many of these substances involve not only increased open probability but also increased single-channel conductance when the initial conductance in GABA is low (Ͻ40 pS) (1)(2)(3)(4)(5). Channels transitioning to high conductance states also exhibit significantly longer mean open times, and hence we refer to them as superchannels (5).…”

mentioning

confidence: 99%

Protein interactions involving the γ2 large cytoplasmic loop of GABA _A receptors modulate conductance

et al. 2009

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Native GABA(A) channels display a single-channel conductance ranging between approximately 10 and 90 pS. Diazepam increases the conductance of some of these native channels but never those of recombinant receptors, unless they are coexpressed with GABARAP. This trafficking protein clusters recombinant receptors in the membrane, suggesting that high-conductance channels arise from receptors that are at locally high concentrations. The amphipathic (MA) helix that is present in the large cytoplasmic loop of every subunit of all ligand-gated ion channels mediates protein-protein interactions. Here we report that when applied to inside-out patches, a peptide mimicking the MA helix of the gamma2 subunit (gamma(381-403)) of the GABA(A) receptor abrogates the potentiating effect of diazepam on both endogenous receptors and recombinant GABA(A) receptors coexpressed with GABARAP, by substantially reducing their conductance. The protein interaction disrupted by the peptide did not involve GABARAP, because a shorter peptide (gamma(386-403)) known to compete with the gamma2-GABARAP interaction did not affect the conductance of recombinant alphabetagamma receptors coexpressed with GABARAP. The requirement for receptor clustering and the fact that the gamma2 MA helix is able to self-associate support a mechanism whereby adjacent GABA(A) receptors interact via their gamma2-subunit MA helices, altering ion permeation through each channel. Alteration of ion-channel function arising from dynamic interactions between ion channels of the same family has not been reported previously and highlights a novel way in which inhibitory neurotransmission in the brain may be differentially modulated.

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The neuroactive steroids alphaxalone and pregnanolone increase the conductance of single GABAA channels in newborn rat hippocampal neurons

Cited by 10 publications

References 36 publications

Activation of α7 Nicotinic Receptors by Orthosteric and Allosteric Agonists: Influence on Single-Channel Kinetics and Conductance

Activation of α7 Nicotinic Receptors by Orthosteric and Allosteric Agonists: Influence on Single-Channel Kinetics and Conductance

Molecular mechanisms of antiseizure drug activity at GABAA receptors

Protein interactions involving the γ2 large cytoplasmic loop of GABA _A receptors modulate conductance

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The neuroactive steroids alphaxalone and pregnanolone increase the conductance of single GABAA channels in newborn rat hippocampal neurons

Cited by 10 publications

References 36 publications

Activation of α7 Nicotinic Receptors by Orthosteric and Allosteric Agonists: Influence on Single-Channel Kinetics and Conductance

Activation of α7 Nicotinic Receptors by Orthosteric and Allosteric Agonists: Influence on Single-Channel Kinetics and Conductance

Molecular mechanisms of antiseizure drug activity at GABAA receptors

Protein interactions involving the γ2 large cytoplasmic loop of GABA A receptors modulate conductance

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Product

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Protein interactions involving the γ2 large cytoplasmic loop of GABA _A receptors modulate conductance