Mechanisms of Barbiturate Inhibition of Acetylcholine Receptor Channels

Dilger, James P.; Boguslavsky, Rebecca; Barann, Martin; Katz, Tamir; Vidal, Ana Maria

doi:10.1085/jgp.109.3.401

Cited by 64 publications

(42 citation statements)

References 29 publications

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“…The [Cu 2ϩ ] cis -induced changes in these parameters were fitted with two or three exponentials. These findings are in agreement with those fits where drugs typically induce open channel block (18).…”

Section: Effects On A␤(1-42) Channel Kinetics Within the Burstsupporting

confidence: 92%

“…The Cu 2ϩ -induced changes in the kinetics of the bursts and the events within the burst are described at least by two exponentials. This behavior appears to be in agreement with that of open channel blocking drugs, which exhibit a two-phase change in current kinetics (18), suggesting that Cu 2ϩ may act on both open and closed states of the channel. Cu 2ϩ also affects desensitization of the A␤(1-42) channels (Fig.…”

Section: Discussionsupporting

confidence: 80%

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Cu²⁺-induced modification of the kinetics of Aβ(1-42) channels

Bahadi

Farrelly²,

Kenna³

et al. 2003

American Journal of Physiology-Cell Physiology

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We found that the amyloid ␤ peptide A␤(1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu 2ϩ or biological redox agents that have been reported to mediate A␤(1-42) toxicity. binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu 2ϩ -binding site of the A␤(1-42)-formed channels is modulated with Cu 2ϩ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu 2ϩ modulation of A␤ and PrP channel proteins linked to neurodegenerative diseases. neurodegenerative diseases; transitional metals; ion channel pathologies; membrane injuries; calcium homeostasis ALZHEIMER'S DISEASE (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The major components of the extracellular neurofibrillar bundles are polymerized amyloid ␤ (A␤) peptides A␤(1-40), A␤(1-42), and A␤(1-43). It has been shown that A␤ familial AD-linked mutations of the amyloid protein precursors presenilin-1 and presenilin-2 increase the concentration of A␤(1-42) (53), which has been shown to be toxic in primary neuronal culture at micromolar concentrations (56). The major mechanisms proposed for A␤-induced cytotoxicity involve the loss of Ca 2ϩ homeostasis (see Refs. 46 and 47) and the generation of reactive oxygen species (see Refs. 9,11,12,and 25). The changes in Ca 2ϩ homeostasis could be the result of 1) alterations in endogenous ion transport systems and 2) formation of heterogeneous ion channels (see Refs. 32,33,and 35). Several laboratories have found that A␤(1-40) and other fragments of amyloid precursor protein that contain A␤ also possess the ability to form ion channels in both artificial and biological membranes. Electrophysiological studies have shown that A␤ fragments, e.g., A␤(25-35), A␤(1-40), and A␤(1-42), elicit cation-selective currents when reconstituted into lipid bilayers (1-4, 23, 24, 30, 35, 37, 41, 55) and in the plasma membrane of neurons (28,29,48) as well as in Xenopus oocytes (21). A␤(1-42) and A␤(1-40) increase Ca 2ϩ uptake in liposomes in a dose-dependent manner (38, 49), and soluble A␤s induce Ca 2ϩ influx in neurons and nonneuronal cells (10,50,51,57).In addition to the A␤ being linked to AD, a role for transition metals has also been recognized. Cu 2ϩ and Zn 2ϩ have been implicated in AD (11,12,42), Parkinson's disease (54), prion protein (PrP) (26), and immunoglobulin light chain amyloidosis (17). The mechanisms underlying the interaction between A␤ and these metals may mediate their role in neurotoxicity. There is also evidence to show that A␤, and also PrP, binds Cu 2ϩ (5, 6) to a si...

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Section: Effects On A␤(1-42) Channel Kinetics Within the Burstsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 80%

Cu²⁺-induced modification of the kinetics of Aβ(1-42) channels

Bahadi

Farrelly²,

Kenna³

et al. 2003

American Journal of Physiology-Cell Physiology

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“…Our findings can be explained by the fact that the blocked receptor may close, with or without trapping the blocker molecule in its site (37,38). Another alternative explanation could be related to the presence of two or more sequential blocking sites in the pore (39,40). In agreement with this, studies of the action of the anthelmintic morantel at the muscle AChR from Ascaris have suggested a complex channel blockade mechanism that could be explained by the presence of two blocking sites within the channel pore (41).…”

Section: Achrs By Levamisolementioning

confidence: 68%

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Rayes

Rosa

Bartos

et al. 2004

Journal of Biological Chemistry

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Levamisole is an anthelmintic agent that exerts its therapeutic effect by acting as a full agonist of the nicotinic receptor (AChR) of nematode muscle. Its action at the mammalian muscle AChR has not been elucidated to date despite its wide use as an anthelmintic in humans and cattle. By single channel and macroscopic current recordings, we investigated the interaction of levamisole with the mammalian muscle AChR. Levamisole activates mammalian AChRs. However, single channel openings are briefer than those activated by acetylcholine (ACh) and do not appear in clusters at high concentrations. The peak current induced by levamisole is about 3% that activated by ACh. Thus, the anthelmintic acts as a weak agonist of the mammalian AChR. Levamisole also produces open channel blockade of the AChR. The apparent affinity for block (190 M at ؊70 mV) is similar to that of the nematode AChR, suggesting that differences in channel activation kinetics govern the different sensitivity of nematode and mammalian muscle to anthelmintics. To identify the structural basis of this different sensitivity, we performed mutagenesis targeting residues in the ␣ subunit that differ between vertebrates and nematodes. The replacement of the conserved ␣Gly-153 with the homologous glutamic acid of nematode AChR significantly increases the efficacy of levamisole to activate channels. Channel activity takes place in clusters having two different kinetic modes. The kinetics of the high open probability mode are almost identical when the agonist is ACh or levamisole. It is concluded that ␣Gly-153 is involved in the low efficacy of levamisole to activate mammalian muscle AChRs.At the neuromuscular junction, acetylcholine (ACh) 1 mediates fast neurotransmission by activating nicotinic receptors (AChRs). AChRs in nematode muscle are targets for anthelmintic chemotherapy. Levamisole and pyrantel are two widely used anthelmintic drugs. By binding to the AChR they lead to a depolarization of the somatic muscle of nematodes. The efficacy of these drugs is based on their ability to act as full agonists of AChRs in nematodes (1). Contractility and membrane potential measurements have shown that the nematode axial muscle is 10 -100 times more sensitive to the acute action of pyrantel and levamisole than the rat muscle (2). The molecular bases of this selectivity have not been yet elucidated. The kinetics of activation of nematode AChRs by levamisole has been studied in several preparations from parasite muscle (1, 3), but its action on mammalian muscle AChRs has not been described to date. The effects of levamisole on human neuronal ␣ 3 ␤ 2 and ␣ 3 ␤ 4 AChRs have been studied recently (4) with the voltage clamp method. It was shown that levamisole behaves as a weak partial agonist, an allosteric modulator, and an open channel blocker of neuronal AChRs (4).ACh is responsible for neuromuscular transmission in nematodes (1). In Caenorhabditis elegans muscle, levamisoleactivated AChRs are composed of the unc-38 subunit, which encodes an ␣ subunit, and lev-1 and...

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“…By contrast, photolabeling at M2-9 was either not inhibited or potentiated, which indicates that [ 3 H]R-mTFD-MPAB can bind in the ion channel near M2-9 and M2-13 when pentobarbital binds at the level of M2-2 and M2-6. Analysis of the inhibition of mouse muscle nAChR by pentobarbital and barbital indicated that they do not compete for a single site but that the binding of one destabilized the other (Dilger et al, 1997). Our results provide the first evidence that two barbiturates can bind simultaneously and in close proximity in the ion channel.…”

mentioning

confidence: 64%

“…Barbiturates act as positive allosteric modulators of GABA A Rs (MacDonald and Olsen, 1994;Löscher and Rogawski, 2012), the in vivo target for many of the anesthetic actions of pentobarbital (Zeller et al, 2007). On the other hand, barbiturates act as noncompetitive/ allosteric inhibitors of muscle-type nAChRs, as shown using electrophysiological (Gage and McKinnon, 1985;Dilger et al, 1997;Krampfl et al, 2000) and ion flux assays (de Armendi et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Identifying Barbiturate Binding Sites in a Nicotinic Acetylcholine Receptor with [³H]Allyl m-Trifluoromethyldiazirine Mephobarbital, a Photoreactive Barbiturate

et al. 2014

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At concentrations that produce anesthesia, many barbituric acid derivatives act as positive allosteric modulators of inhibitory GABA A receptors (GABA A Rs) and inhibitors of excitatory nicotinic acetylcholine receptors (nAChRs). Recent research on [ 3 H]R-mTFD-MPAB in the nAChR transmembrane domain: 1) a site within the ion channel, identified by photolabeling in the nAChR desensitized state of amino acids within the M2 helices of each nAChR subunit; and 2) a site at the g-a subunit interface, identified by photolabeling of gMet299 within the gM3 helix at similar efficiency in the resting and desensitized states. These results establish that mTFD-MPAB is a potent nAChR inhibitor that binds in the ion channel preferentially in the desensitized state and binds with lower affinity to a site at the g-a subunit interface where etomidate analogs bind that act as positive and negative nAChR modulators.

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Mechanisms of Barbiturate Inhibition of Acetylcholine Receptor Channels

Cited by 64 publications

References 29 publications

Cu²⁺-induced modification of the kinetics of Aβ(1-42) channels

Cu²⁺-induced modification of the kinetics of Aβ(1-42) channels

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Identifying Barbiturate Binding Sites in a Nicotinic Acetylcholine Receptor with [³H]Allyl m-Trifluoromethyldiazirine Mephobarbital, a Photoreactive Barbiturate

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Mechanisms of Barbiturate Inhibition of Acetylcholine Receptor Channels

Cited by 64 publications

References 29 publications

Cu2+-induced modification of the kinetics of Aβ(1-42) channels

Cu2+-induced modification of the kinetics of Aβ(1-42) channels

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole

Identifying Barbiturate Binding Sites in a Nicotinic Acetylcholine Receptor with [3H]Allyl m-Trifluoromethyldiazirine Mephobarbital, a Photoreactive Barbiturate

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Cu²⁺-induced modification of the kinetics of Aβ(1-42) channels

Cu²⁺-induced modification of the kinetics of Aβ(1-42) channels

Identifying Barbiturate Binding Sites in a Nicotinic Acetylcholine Receptor with [³H]Allyl m-Trifluoromethyldiazirine Mephobarbital, a Photoreactive Barbiturate