Interaction of d-Tubocurarine Analogs with the Torpedo Nicotinic Acetylcholine Receptor:

Pedersen, Steen E.; Papineni, Rao

doi:10.1074/jbc.270.52.31141

Journal of Biological Chemistry

1995

DOI: 10.1074/jbc.270.52.31141

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Interaction of d-Tubocurarine Analogs with the Torpedo Nicotinic Acetylcholine Receptor:

Steen E. Pedersen

Rao Papineni

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Cited by 24 publications

(34 citation statements)

References 40 publications

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“…1. For both mouse and Torpedo AChR, we demonstrated that the stereochemistry at the 1 carbon was important for high affinity binding but that the ammoniums at the 2-and 2Ј-positions need not be quaternary for high affinity binding (21). Furthermore, dTC ring D, which includes the 12Ј-and 13Ј-positions, interacts in a siteselective manner, consistent with a possible interaction with the ␥-and ␦-subunits.…”

mentioning

confidence: 64%

“…Our previous studies (21,22) have taken advantage of dTC analogs to examine the importance of various functional groups to binding interactions and conformational transitions. The structures of the analogs are shown in Fig.…”

mentioning

confidence: 99%

“…In this study, we utilize a double mutant thermodynamic cycle analysis to analyze the interaction between our library of dTC analogs (21) and residues in the AChR-binding site, with particular emphasis on the interaction with residue ␥Tyr 117 . We demonstrate that both the 2-N and the 13Ј-positions of dTC appear to interact with this amino acid but with a proximal interaction only to the 2-N. Based on this conclusion and using the structure of the AChBP, we present a plausible structural model for the orientation and position of dTC within the binding pocket.…”

mentioning

confidence: 99%

“…Synthesis of d-Tubocurarine Analogs-Synthesis of most of the dtubocurarine analogs was described previously (21). Synthesis of several new analogs is described as follows.…”

mentioning

confidence: 99%

“…Cells were returned to the incubator and harvested 48 -72 h after transfection. I-␣-BgTx to Torpedo AChR was carried out as described previously (21). For determination of binding constants to mutant mouse AChR expressed in tissue culture cells, the following protocol was observed.…”

mentioning

confidence: 99%

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Orientation of d-Tubocurarine in the Muscle Nicotinic Acetylcholine Receptor-binding Site

Willcockson¹,

Hong²,

Whisenant³

et al. 2002

Journal of Biological Chemistry

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Ligand modification and receptor site-directed mutagenesis were used to examine binding of the competitive antagonist, d-tubocurarine (dTC), to the muscletype nicotinic acetylcholine receptor (AChR). By using various dTC analogs, we measured the interactions of specific dTC functional groups with amino acid positions in the AChR ␥-subunit. Because data for mutations at residue ␥Tyr 117 were the most consistent with direct interaction with dTC, we focused on that residue. Double mutant thermodynamic cycle analysis showed apparent interactions of ␥Tyr

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mentioning

confidence: 64%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Synthesis of d-Tubocurarine Analogs-Synthesis of most of the dtubocurarine analogs was described previously (21). Synthesis of several new analogs is described as follows.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Orientation of d-Tubocurarine in the Muscle Nicotinic Acetylcholine Receptor-binding Site

Willcockson¹,

Hong²,

Whisenant³

et al. 2002

Journal of Biological Chemistry

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Characterization of nicotinic acetylcholine receptors from the insectsAphis craccivora,Myzus persicae, andLocusta migratoria by radioligand binding assays: Relation to thiamethoxam action

Wiesner

Kayser

2000

J. Biochem. Mol. Toxicol.

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Thiamethoxam, a new neonicotinoid insecticide acting at nicotinic acetylcholine receptors, was characterized in competition binding assays with [3‐H]‐imidacloprid, a specific nicotinic ligand, using membranes from the aphids Aphis craccivora and Myzus persicae, and from the locust Locusta migratoria. In all insects, Scatchard analysis suggested two binding sites for imidacloprid with Kd values in the range of 1 nM and 10 nM, respectively. The Hill values were significantly below 1 (range of 0.63 to 0.85). In contrast to imidacloprid and nicotine, the potency of thiamethoxam to displace [3‐H]‐imidacloprid varied considerably among these insects. Thiamethoxam was more active than nicotine on Aphis receptors but 100‐fold less in Locusta, a nontarget insect. Comparable relations were found to nithiazine. In Myzus, the inhibition curve for thiamethoxam was shallow. This suggested a heterogeneous receptor population displaying a range of binding affinities to thiamethoxam in this aphid. In all three insects, the other neonicotinoid insecticides studied competed with [3‐H]‐imidacloprid in the same order: thiacloprid > imidacloprid ≥ acetamiprid > nitenpyram. N‐Methylation of imidacloprid strongly reduced the affinity to the imidacloprid site, whereas N‐demethylation of thiamethoxam resulted in a comparable increase of affinity. Supplementary assays were performed with (−)‐[3‐H]‐nicotine and [3‐H]‐α‐bungarotoxin on locust membranes. Overall, the data suggested that the outstanding insecticidal properties of thiamethoxam may be due to either a different binding site on nicotinic receptors, or receptor isoforms, or specific pharmakokinetic behavior, rather than to exceptional affinity to one of the examined binding sites. © 2000 John Wiley & Sons, Inc. J Biochem Toxicol 14:221–230, 2000

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Mode of cembranoid action on embryonic muscle acetylcholine receptor

Ulrich¹,

Nery²,

Trujillo³

et al. 2007

J of Neuroscience Research

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The mechanism of eupalmerin acetate (EUAC) actions on the embryonic muscle nicotinic acetylcholine receptor (nAChR) in BC3H-1 cells was studied by using whole-cell and single-channel patch-clamp current measurements. With whole-cell currents, EUAC did not act as an agonist on this receptor. Coapplication of 30 microM EUAC with 50 microM, 100 microM, or 500 microM carbamoylcholine (CCh) reversibly inhibited the current amplitude, whereas, with 20 microM CCh, current was increased above control values in the presence of EUAC. EUAC concentration curves (0.01-40 microM) obtained with 100 microM and 500 microM CCh displayed slope coefficients, n(H), significantly smaller than one, suggesting that EUAC bound to several sites with widely differing affinities on the receptor molecule. The apparent rate of receptor desensitization in the presence of EUAC and CCh was either slower than or equal to that obtained with CCh alone. The major finding from single-channel studies was that EUAC did not affect single-channel conductance or the ability of CCh to interact with the receptor. Instead, EUAC acted by increasing the channel closing rate constant. The results are not consistent with the competitive model for EUAC inhibition, with the sequential open-channel block model, or with inhibition by increased desensitization. The data are best accounted for by a model in which EUAC acts by closed-channel block at low concentrations, by positive modulation at intermediate concentrations, and by negative allosteric modulation of the open channel at high concentrations.

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Interaction of d-Tubocurarine Analogs with the Torpedo Nicotinic Acetylcholine Receptor:

Cited by 24 publications

References 40 publications

Orientation of d-Tubocurarine in the Muscle Nicotinic Acetylcholine Receptor-binding Site

Orientation of d-Tubocurarine in the Muscle Nicotinic Acetylcholine Receptor-binding Site

Characterization of nicotinic acetylcholine receptors from the insectsAphis craccivora,Myzus persicae, andLocusta migratoria by radioligand binding assays: Relation to thiamethoxam action

Mode of cembranoid action on embryonic muscle acetylcholine receptor

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