Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors. / Brier, Tim J; Mellor, Ian R; Tikhonov, Denis B; Neagoe, Ioana; Shao, Zuoyi; Brierley, Matt J; Strømgaard, Kristian; Jaroszewski, Jerzy W; Krogsgaard-Larsen, Povl; Usherwood, Peter N R.

In: Molecular Pharmacology, Vol. 64, No. 4, 10.2003, p. 954-964.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Brier, TJ, Mellor, IR, Tikhonov, DB, Neagoe, I, Shao, Z, Brierley, MJ, Strømgaard, K, Jaroszewski, JW, Krogsgaard-Larsen, P & Usherwood, PNR 2003, 'Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors', Molecular Pharmacology, vol. 64, no. 4, pp. 954-964. https://doi.org/10.1124/mol.64.4.954

APA

Brier, T. J., Mellor, I. R., Tikhonov, D. B., Neagoe, I., Shao, Z., Brierley, M. J., Strømgaard, K., Jaroszewski, J. W., Krogsgaard-Larsen, P., & Usherwood, P. N. R. (2003). Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors. Molecular Pharmacology, 64(4), 954-964. https://doi.org/10.1124/mol.64.4.954

Vancouver

Brier TJ, Mellor IR, Tikhonov DB, Neagoe I, Shao Z, Brierley MJ et al. Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors. Molecular Pharmacology. 2003 Oct;64(4):954-964. https://doi.org/10.1124/mol.64.4.954

Author

Brier, Tim J ; Mellor, Ian R ; Tikhonov, Denis B ; Neagoe, Ioana ; Shao, Zuoyi ; Brierley, Matt J ; Strømgaard, Kristian ; Jaroszewski, Jerzy W ; Krogsgaard-Larsen, Povl ; Usherwood, Peter N R. / Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors. In: Molecular Pharmacology. 2003 ; Vol. 64, No. 4. pp. 954-964.

Bibtex

@article{50bc6d96f1ae406698ee7e260af93785,
title = "Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors",
abstract = "Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, PhTX-343 and PhTX-(12). When coapplied with acetylcholine (ACh), PhTX-343 caused activation-dependent, noncompetitive inhibition (IC50 = 17 microM at -100 mV) of whole-cell currents that was strongly voltage-dependent. However, preapplication of PhTX-343 unveiled a voltage-independent antagonism that also required receptor activation, which is suggestive of desensitization enhancement. In single-channel studies, 10 microM PhTX-343 significantly reduced the mean open time of channel openings evoked by 1 microM ACh from 4.42 +/- 0.44 to 1.58 +/- 0.10 ms with a minor increase (1.26-fold) in mean closed time. These data indicate that PhTX-343 predominantly blocks the open channel gated by ACh. In contrast, PhTX-(12) caused potent (IC50 = 0.77 microM at-100 mV), activation-dependent, noncompetitive inhibition of ACh-induced whole-cell currents that was only weakly voltage-dependent and suggestive of desensitization enhancement. It caused only a small decrease (7.5%) in the mean open time of channel openings induced by 1 microM ACh, whereas the mean closed time was significantly increased from 200 +/- 45 ms to 586 +/- 145 ms. The different voltage-dependencies of the two modes of action of these philanthotoxins suggest two binding sites, one deep in the nAChR pore, the other near the extracellular entrance to the pore.",
keywords = "Cells, Cultured, Humans, Phenols, Polyamines, Receptors, Nicotinic, Tyrosine",
author = "Brier, {Tim J} and Mellor, {Ian R} and Tikhonov, {Denis B} and Ioana Neagoe and Zuoyi Shao and Brierley, {Matt J} and Kristian Str{\o}mgaard and Jaroszewski, {Jerzy W} and Povl Krogsgaard-Larsen and Usherwood, {Peter N R}",
year = "2003",
month = oct,
doi = "10.1124/mol.64.4.954",
language = "English",
volume = "64",
pages = "954--964",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

RIS

TY - JOUR

T1 - Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors

AU - Brier, Tim J

AU - Mellor, Ian R

AU - Tikhonov, Denis B

AU - Neagoe, Ioana

AU - Shao, Zuoyi

AU - Brierley, Matt J

AU - Strømgaard, Kristian

AU - Jaroszewski, Jerzy W

AU - Krogsgaard-Larsen, Povl

AU - Usherwood, Peter N R

PY - 2003/10

Y1 - 2003/10

N2 - Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, PhTX-343 and PhTX-(12). When coapplied with acetylcholine (ACh), PhTX-343 caused activation-dependent, noncompetitive inhibition (IC50 = 17 microM at -100 mV) of whole-cell currents that was strongly voltage-dependent. However, preapplication of PhTX-343 unveiled a voltage-independent antagonism that also required receptor activation, which is suggestive of desensitization enhancement. In single-channel studies, 10 microM PhTX-343 significantly reduced the mean open time of channel openings evoked by 1 microM ACh from 4.42 +/- 0.44 to 1.58 +/- 0.10 ms with a minor increase (1.26-fold) in mean closed time. These data indicate that PhTX-343 predominantly blocks the open channel gated by ACh. In contrast, PhTX-(12) caused potent (IC50 = 0.77 microM at-100 mV), activation-dependent, noncompetitive inhibition of ACh-induced whole-cell currents that was only weakly voltage-dependent and suggestive of desensitization enhancement. It caused only a small decrease (7.5%) in the mean open time of channel openings induced by 1 microM ACh, whereas the mean closed time was significantly increased from 200 +/- 45 ms to 586 +/- 145 ms. The different voltage-dependencies of the two modes of action of these philanthotoxins suggest two binding sites, one deep in the nAChR pore, the other near the extracellular entrance to the pore.

AB - Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, PhTX-343 and PhTX-(12). When coapplied with acetylcholine (ACh), PhTX-343 caused activation-dependent, noncompetitive inhibition (IC50 = 17 microM at -100 mV) of whole-cell currents that was strongly voltage-dependent. However, preapplication of PhTX-343 unveiled a voltage-independent antagonism that also required receptor activation, which is suggestive of desensitization enhancement. In single-channel studies, 10 microM PhTX-343 significantly reduced the mean open time of channel openings evoked by 1 microM ACh from 4.42 +/- 0.44 to 1.58 +/- 0.10 ms with a minor increase (1.26-fold) in mean closed time. These data indicate that PhTX-343 predominantly blocks the open channel gated by ACh. In contrast, PhTX-(12) caused potent (IC50 = 0.77 microM at-100 mV), activation-dependent, noncompetitive inhibition of ACh-induced whole-cell currents that was only weakly voltage-dependent and suggestive of desensitization enhancement. It caused only a small decrease (7.5%) in the mean open time of channel openings induced by 1 microM ACh, whereas the mean closed time was significantly increased from 200 +/- 45 ms to 586 +/- 145 ms. The different voltage-dependencies of the two modes of action of these philanthotoxins suggest two binding sites, one deep in the nAChR pore, the other near the extracellular entrance to the pore.

KW - Cells, Cultured

KW - Humans

KW - Phenols

KW - Polyamines

KW - Receptors, Nicotinic

KW - Tyrosine

U2 - 10.1124/mol.64.4.954

DO - 10.1124/mol.64.4.954

M3 - Journal article

C2 - 14500752

VL - 64

SP - 954

EP - 964

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 4

ER -

ID: 45810179