Research

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


Reference:

Mogg, A. J., Whiteaker, P., McIntosh, J. M., Marks, M., Collins, A. C. and Wonnacott, S., 2002. Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. Journal of Pharmacology and Experimental Therapeutics, 302 (1), pp. 197-204.

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Official URL:

http://dx.doi.org/10.1124/jpet.302.1.197

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.

Details

Item Type Articles
CreatorsMogg, A. J., Whiteaker, P., McIntosh, J. M., Marks, M., Collins, A. C. and Wonnacott, S.
DOI10.1124/jpet.302.1.197
DepartmentsFaculty of Science > Biology & Biochemistry
RefereedYes
StatusPublished
ID Code4195

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