Studies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ

Grünhagen, Hans-Heinrich; Changeux, Jean‐Pierre

doi:10.1016/0022-2836(76)90250-3

Cited by 57 publications

(17 citation statements)

References 15 publications

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“…At this concentration-range, mepacrine inhibited acetylcholine bindings to muscarinic (O'Donnell & Howlett, 1991) and nicotinic receptors (Grunhagen & Changeux, 1976;Cox et al, 1985), decreased voltage-gated Ca2+ currents (Mironov & Lux, 1992;Sargent et al, 1992) and a fast transient outward K+ current (Kehl, 1991), depressed Na+/Ca2" and Na+/H' exchange (Shepherd et al, 1991;Karmazyn et at., 1990) and had a cardioprotective effect against ischaemia (Chiariello et al, 1987;Sargent et al, 1992). All these mepacrine effects were independent of phospholipase A2 activity, although the effective mepacrine concentration for the inhibition of phospholipase A2 is also in this range (Billah et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

“…O'Donnell & Howlett (1991) reported that mepacrine acted at the agonist binding site on acetylcholine muscarinic receptors and shifted the dose-response curve in a parallel fashion. Similarly, mepacrine also acted at the acetylcholine binding site on nicotinic receptors (Grunhagen & Changeux, 1976;Cox et al, 1985), although mepacrine may affect other sites of acetylcholine binding such as acetylcholine uptake protein (Anderson et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

“…A well known example is the effect of local anaesthetics on nicotinic receptors (Neher & Steinbach, 1978). A local anaesthetic-like effect of mepacrine on nicotinic receptors has been reported (Grunhagen & Changeux, 1976). However, our previous results demonstrate that local anesthetics such as cocaine, procaine and tetracaine exhibit a competitive blockade on the activation of 5-HT3 receptors (Fan et al, 1992;Fan & Weight, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…However, mepacrine also has other effects on cellular physiology. It binds to DNA (Darzynkiewicz et al, 1984), increases the pH of lysosomes (DiCerbo et al, 1984), competes with the binding of acetylcholine to muscarinic and nicotinic receptors (O'Donnell & Howlett, 1991;Grunhagen & Changeux, 1976;Cox et al, 1985) and may have local anaesthetic-like actions (Grunhagen & Changeux, 1976). Several studies have shown that mepacrine interacts with voltage-gated ion channels such as the fast transient outward K+ channels in rat melanotrophs (Kehl, 1991) and the high-threshold Ca2+ channel in rat hippocampal cells (Mironov & Lux, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Mepacrine‐induced inhibition of the inward current mediated by 5‐HT₃ receptors in rat nodose ganglion neurones

Fan

1994

British J Pharmacology

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1 With the whole-cell patch clamp technique, the effect of the antimalarial drug, mepacrine (quinacrine) on the inward current mediated by 5-HT3 receptors (5-hydroxytryptamine (5-HT)-induced current) was investigated in isolated nodose ganglion neurones of the rat. 2 5-HT and the selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide elicited an inward current which reversed at around 0 mV and quickly desensitized to a steady state level.3 Mepacrine dose-dependently inhibited the peak current induced by 5-HT with an IC50 of 2.1 jAM and an apparent Hill coefficient of 0.99. 4 Mepacrine increased the decay rate of the 5-HT-induced current. 5 The effect of mepacrine on the 5-HT-induced current was reversible and not dependent on membrane potential. The reversal potential of the 5-HT-induced current was not affected. 6 Intracellular mepacrine had no significant effect on the 5-HT-induced current and did not block the extracellular action of mepacrine. 7 Concentration-response curves in the presence and absence of mepacrine suggest a non-competitive inhibition of 5-HT-induced current by mepacrine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mepacrine‐induced inhibition of the inward current mediated by 5‐HT₃ receptors in rat nodose ganglion neurones

Fan

1994

British J Pharmacology

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“…Quinacrine azide (17), a derivative of the open-channel blocker quinacrine (18)(19)(20), photolabeled residues at the extracellular end of ␣M1 specifically in the open state of the receptor (21)(22)(23). In addition, a number of substituted Cys in the outer third of M1 are accessible from the channel lumen either in the resting state or in the open state (15,24,25).…”

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confidence: 99%

Structural effects of quinacrine binding in the open channel of the acetylcholine receptor

Shi

Karlin

2003

Proc. Natl. Acad. Sci. U.S.A.

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Binding of acetylcholine (ACh) to nicotinic ACh receptors in the resting state leads to an open state and in the continued presence of ACh to a closed, desensitized state (1, 2). These receptors consist of five subunits that are either homologous or identical (3, 4). The subunits have a large extracellular domain, four membrane-spanning segments (M1-M4), and an intracellular domain. The subunits surround a central channel. The structure of the extracellular domain is known in great detail thanks to a wealth of biochemical and mutagenetic results (3, 4), a high-resolution structure of a homopentameric ACh-binding protein homologous to the extracellular domain of the ACh receptor (5), and cryoelectron microscopy of two-dimensional crystals of ACh receptor in membrane (6). The threedimensional structures of the membrane domain and the cytoplasmic domain are less well established.The structure of the membrane domain and the channel have been studied in receptors from electric cells and muscle, subunit composition (␣1) 2 (␤1)␥␦ or (␣1) 2 (␤1)␦, and homopentameric neuronal receptor composition (␣7) 5 (3, 4). The channel lumen is lined by the M2 segments from the five subunits Fig. 1A). Residues in M2 were labeled by photoactivated (9, 10) and electrophilic (11) noncompetitive inhibitors. In addition, mutations of residues in M2 altered the effectiveness of open-channel blockers (12, 13). All of the residues that line the channel lumen in the M2 segments of the mouse-muscle ACh receptor ␣ and ␤ subunits were identified by the substituted cysteine accessibility method, which identifies Cys accessible to water and to small, polar reagents, and the pattern of accessibility conformed largely to an exposed stripe of an ␣-helix (14, 15).Residues in the M1 segments also contribute to the channel lining. Quinacrine azide (17), a derivative of the open-channel blocker quinacrine (18)(19)(20), photolabeled residues at the extracellular end of ␣M1 specifically in the open state of the receptor (21-23). In addition, a number of substituted Cys in the outer third of M1 are accessible from the channel lumen either in the resting state or in the open state (15,24,25). The pattern of accessibility was inconsistent with a regular secondary structure in this region. The accessibility of residues in the outer third of M1 is consistent, at least in the open state, with a funnel-shaped lumen (26) lined with alternating M1 strands and M2 helices at its wide outer end and by just five M2 helices at its narrow inner end ( Fig. 1B; refs. 14, 15, 24, 25, and 27).The narrow inner end of the channel contains rings of aligned residues in the M1-M2 loops and the inner ends of M2 that are the principal determinants of conductance (28), size selectivity (29-31), and charge selectivity (32). The resting (activation) gate has been proposed to be in the middle of the membrane (33) or alternatively at the inner end of the channel (34). Furthermore, the gate in the desensitized state has been proposed to extend from the inner end to the middle of the c...

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Sengbusch

1979

Molekular- Und Zellbiologie

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Studies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ

Cited by 57 publications

References 15 publications

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT₃ receptors in rat nodose ganglion neurones

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT₃ receptors in rat nodose ganglion neurones

Structural effects of quinacrine binding in the open channel of the acetylcholine receptor

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Studies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ

Cited by 57 publications

References 15 publications

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT3 receptors in rat nodose ganglion neurones

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT3 receptors in rat nodose ganglion neurones

Structural effects of quinacrine binding in the open channel of the acetylcholine receptor

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Mepacrine‐induced inhibition of the inward current mediated by 5‐HT₃ receptors in rat nodose ganglion neurones

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT₃ receptors in rat nodose ganglion neurones