Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum

A J Mogg, P Whiteaker, J M McIntosh, M Marks, A C Collins, S Wonnacott

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Abstract

The plant alkaloid methyllycaconitine (MLA) is considered to be a selective antagonist of the alpha7 subtype of neuronal nicotinic acetylcholine receptor (nAChR). However, 50 nM MLA partially inhibited (by 16%) [H-3] dopamine release from rat striatal synaptosomes stimulated with 10 muM nicotine. Other alpha7-selective antagonists had no effect. Similarly, MLA (50 nM) inhibited [H-3] dopamine release evoked by the partial agonist (2-chloro-5-pyridyl)- 9-azabicyclo[4.2.1] non-2-ene (UB-165) (0.2 muM) by 37%. In both cases, inhibition by MLA was surmountable with higher agonist concentrations, indicative of a competitive interaction. At least two subtypes of presynaptic nAChR can modulate dopamine release in the striatum, and these nAChR are distinguished by their differential sensitivity to alpha-conotoxin-MII (alpha-CTx-MII). MLA was not additive with a maximally effective concentration of alpha-CTx-MII (100 nM) in inhibiting [H-3] dopamine release elicited by 10 muM nicotine or 0.2 muM UB-165, suggesting that both toxins act at the same site. This was confirmed in quantitative binding assays with I-125-alpha-CTx-MII, which displayed saturable specific binding to rat striatum and nucleus accumbens with B-max values of 9.8 and 16.5 fmol/mg of protein, and K-d values of 0.63 and 0.83 nM, respectively. MLA fully inhibited I-125-alpha-CTx-MII binding to striatum and nucleus accumbens with a K-i value of 33 nM, consistent with the potency observed in the functional assays. We speculate that MLA and alpha-CTx-MII interact with a presynaptic nAChR of subunit composition alpha3/alpha6beta2beta3* on dopamine neurons. The use of MLA as an alpha7-selective antagonist should be exercised with caution, especially in studies of nAChR in basal ganglia.
LanguageEnglish
Pages197-204
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume302
Issue number1
DOIs
StatusPublished - 1 Jul 2002

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Nicotinic Receptors
Dopamine
Nucleus Accumbens
Nicotine
Corpus Striatum
methyllycaconitine
alpha-conotoxin MII
Synaptosomes
Dopaminergic Neurons
Basal Ganglia
Alkaloids
(2-chloro-5-pyridyl)-9-azabicyclo(4.2.1)non-2-ene

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Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. / Mogg, A J; Whiteaker, P; McIntosh, J M; Marks, M; Collins, A C; Wonnacott, S.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 302, No. 1, 01.07.2002, p. 197-204.

Research output: Contribution to journalArticle

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abstract = "The plant alkaloid methyllycaconitine (MLA) is considered to be a selective antagonist of the alpha7 subtype of neuronal nicotinic acetylcholine receptor (nAChR). However, 50 nM MLA partially inhibited (by 16{\%}) [H-3] dopamine release from rat striatal synaptosomes stimulated with 10 muM nicotine. Other alpha7-selective antagonists had no effect. Similarly, MLA (50 nM) inhibited [H-3] dopamine release evoked by the partial agonist (2-chloro-5-pyridyl)- 9-azabicyclo[4.2.1] non-2-ene (UB-165) (0.2 muM) by 37{\%}. In both cases, inhibition by MLA was surmountable with higher agonist concentrations, indicative of a competitive interaction. At least two subtypes of presynaptic nAChR can modulate dopamine release in the striatum, and these nAChR are distinguished by their differential sensitivity to alpha-conotoxin-MII (alpha-CTx-MII). MLA was not additive with a maximally effective concentration of alpha-CTx-MII (100 nM) in inhibiting [H-3] dopamine release elicited by 10 muM nicotine or 0.2 muM UB-165, suggesting that both toxins act at the same site. This was confirmed in quantitative binding assays with I-125-alpha-CTx-MII, which displayed saturable specific binding to rat striatum and nucleus accumbens with B-max values of 9.8 and 16.5 fmol/mg of protein, and K-d values of 0.63 and 0.83 nM, respectively. MLA fully inhibited I-125-alpha-CTx-MII binding to striatum and nucleus accumbens with a K-i value of 33 nM, consistent with the potency observed in the functional assays. We speculate that MLA and alpha-CTx-MII interact with a presynaptic nAChR of subunit composition alpha3/alpha6beta2beta3* on dopamine neurons. The use of MLA as an alpha7-selective antagonist should be exercised with caution, especially in studies of nAChR in basal ganglia.",
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T1 - Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum

AU - Mogg,A J

AU - Whiteaker,P

AU - McIntosh,J M

AU - Marks,M

AU - Collins,A C

AU - Wonnacott,S

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N2 - The plant alkaloid methyllycaconitine (MLA) is considered to be a selective antagonist of the alpha7 subtype of neuronal nicotinic acetylcholine receptor (nAChR). However, 50 nM MLA partially inhibited (by 16%) [H-3] dopamine release from rat striatal synaptosomes stimulated with 10 muM nicotine. Other alpha7-selective antagonists had no effect. Similarly, MLA (50 nM) inhibited [H-3] dopamine release evoked by the partial agonist (2-chloro-5-pyridyl)- 9-azabicyclo[4.2.1] non-2-ene (UB-165) (0.2 muM) by 37%. In both cases, inhibition by MLA was surmountable with higher agonist concentrations, indicative of a competitive interaction. At least two subtypes of presynaptic nAChR can modulate dopamine release in the striatum, and these nAChR are distinguished by their differential sensitivity to alpha-conotoxin-MII (alpha-CTx-MII). MLA was not additive with a maximally effective concentration of alpha-CTx-MII (100 nM) in inhibiting [H-3] dopamine release elicited by 10 muM nicotine or 0.2 muM UB-165, suggesting that both toxins act at the same site. This was confirmed in quantitative binding assays with I-125-alpha-CTx-MII, which displayed saturable specific binding to rat striatum and nucleus accumbens with B-max values of 9.8 and 16.5 fmol/mg of protein, and K-d values of 0.63 and 0.83 nM, respectively. MLA fully inhibited I-125-alpha-CTx-MII binding to striatum and nucleus accumbens with a K-i value of 33 nM, consistent with the potency observed in the functional assays. We speculate that MLA and alpha-CTx-MII interact with a presynaptic nAChR of subunit composition alpha3/alpha6beta2beta3* on dopamine neurons. The use of MLA as an alpha7-selective antagonist should be exercised with caution, especially in studies of nAChR in basal ganglia.

AB - The plant alkaloid methyllycaconitine (MLA) is considered to be a selective antagonist of the alpha7 subtype of neuronal nicotinic acetylcholine receptor (nAChR). However, 50 nM MLA partially inhibited (by 16%) [H-3] dopamine release from rat striatal synaptosomes stimulated with 10 muM nicotine. Other alpha7-selective antagonists had no effect. Similarly, MLA (50 nM) inhibited [H-3] dopamine release evoked by the partial agonist (2-chloro-5-pyridyl)- 9-azabicyclo[4.2.1] non-2-ene (UB-165) (0.2 muM) by 37%. In both cases, inhibition by MLA was surmountable with higher agonist concentrations, indicative of a competitive interaction. At least two subtypes of presynaptic nAChR can modulate dopamine release in the striatum, and these nAChR are distinguished by their differential sensitivity to alpha-conotoxin-MII (alpha-CTx-MII). MLA was not additive with a maximally effective concentration of alpha-CTx-MII (100 nM) in inhibiting [H-3] dopamine release elicited by 10 muM nicotine or 0.2 muM UB-165, suggesting that both toxins act at the same site. This was confirmed in quantitative binding assays with I-125-alpha-CTx-MII, which displayed saturable specific binding to rat striatum and nucleus accumbens with B-max values of 9.8 and 16.5 fmol/mg of protein, and K-d values of 0.63 and 0.83 nM, respectively. MLA fully inhibited I-125-alpha-CTx-MII binding to striatum and nucleus accumbens with a K-i value of 33 nM, consistent with the potency observed in the functional assays. We speculate that MLA and alpha-CTx-MII interact with a presynaptic nAChR of subunit composition alpha3/alpha6beta2beta3* on dopamine neurons. The use of MLA as an alpha7-selective antagonist should be exercised with caution, especially in studies of nAChR in basal ganglia.

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