The charge carried by single‐channel currents of rat cultured muscle cells in the presence of local anaesthetics.

Neher, Erwin

doi:10.1113/jphysiol.1983.sp014741

Cited by 216 publications

(184 citation statements)

References 24 publications

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“…the receptor-channel complex rather than by physically blocking channels. Several other drugs thought to have been simple channel blockers have also been found not to act in this way (Gage & Sah, 1982;Gage et al, 1983;Neher, 1983;Gage & Wachtel, 1984).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

Gage

McKinnon

1985

British J Pharmacology

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Section: Introductionmentioning

confidence: 99%

“…The cumulative distribution of open and closed times could be calculated directly from the measured transition times. To calculate the burst length distribution, a critical closed time was calculated using a procedure similar to that of Magleby & Pallotta (1983 (Neher, 1983 Figure 3a). Figure 3b).…”

Section: Introductionmentioning

confidence: 99%

Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

Gage

McKinnon

1985

British J Pharmacology

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“…Deviations from the linear open channel block mechanism have been also described for many noncompetitive antagonists at high concentrations (35,36). 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).…”

Section: Achrs By Levamisolementioning

confidence: 52%

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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“…While burst duration increased in the presence of QX-222, conduction time within a burst decreased from 2.3 ms (control) to 2.2 ms (100 JM QX-222) in the same patches. The equilibrium dissociation constant (Qd) may be estimated from the burst duration (T) and total conduction time (T') (Neher, 1983) …”

Section: Single-channel Recordingsmentioning

confidence: 99%

Local anaesthetic blockade of neuronal nicotinic ACh receptor‐channels in rat parasympathetic ganglion cells

Cuevas

Adams

1994

British J Pharmacology

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1 The effects of the local anaesthetics QX-222 and procaine on nicotinic acetylcholine (ACh)-evoked currents in cultured parasympathetic cardiac neurones of the rat were investigated by use of the whole-cell, perforated-patch, and outside-out recording configurations of the patch clamp method. 2 QX-222 and procaine, applied to the extracellular surface, reversibly inhibited the peak amplitude of the whole-cell nicotinic ACh-evoked current in a concentration-dependent manner, with half-maximal inhibitory concentrations (IC50) of 28 pM and 2.8 pLM, respectively, at -80 mV. In these neurones, the sustained inward current mediated by Ml muscarinic receptor activation was unaltered by QX-222, and neither local anaesthetic affected the adenosine 5'-triphosphate (ATP)-evoked current. 3 QX-222 and procaine block of nicotinic ACh-evoked inward current was voltage-dependent and enhanced by hyperpolarization. An e-fold change in their dissociation equilibrium constants (Kd) resulted from a 62 mV and a 122 mV change in membrane potential, respectively. 4 Both local anaesthetics produce a concentration-dependent increase in the half-time of decay of the nicotinic ACh-evoked inward current. 5 Measurements of unitary currents in outside-out patches showed that QX-222 reversibly increased the mean burst duration and closed time and reduced the mean channel open time and open-state probability of the nicotinic ACh receptor-channel (AChR) in a concentration-dependent manner. 6 The Kd and voltage sensitivity of local anaesthetic block of the nicotinic AChR in rat intracardiac neurones suggests that the pore-forming region of this channel differs from that of the AChR in frog and rat skeletal muscle and from the neuronal a42 ACh receptor-channel.

show abstract

The charge carried by single‐channel currents of rat cultured muscle cells in the presence of local anaesthetics.

Cited by 216 publications

References 24 publications

Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

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

Local anaesthetic blockade of neuronal nicotinic ACh receptor‐channels in rat parasympathetic ganglion cells

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