Alpha-conotoxin MII blocks nicotine-stimulated dopamine release in rat striatal synaptosomes.
Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) can induce the release of neurotransmitters such as dopamine and norepinephrine in the CNS. Accumulating evidence suggests that distinct nAChR subtypes are involved; however, it has been difficult to determine the subunit composition of these receptors, in part because of the lack of a sufficient variety of selective nAChR ligands. We present experimental data that at least two different nAChR complexes are involved in dopamine release, one of which has an alpha3/beta2 subunit interface. The recently discovered peptide alpha-conotoxin MII is a potent and selective inhibitor of rat nAChRs containing an interface formed by alpha3 and beta2 subunits. We used this peptide to examine nicotine-stimulated release of dopamine from rat striatal synaptosomes and of norepinephrine from hippocampal synaptosomes. MII (100 nM) blocks 34-49% of the nicotine-stimulated dopamine release, but not dopamine release evoked by elevated [K+]. Furthermore, two peptides structurally related to alpha-conotoxin MII, namely alpha-conotoxin MI (selective for alpha1beta1gammadelta nAChRs) and alpha-conotoxin ImI (selective for alpha7-containing nAChRs), have no effect on nicotine-stimulated dopamine release. The results indicate that one third to half of the dopamine release in the striatal preparation is mediated by nAChRs with an alpha3/beta2 subunit interface. In contrast, </=10% of nicotine-stimulated release of norepinephrine from hippocampal synaptosomes is modulated by nAChRs with alpha3/beta2 subunit interfaces.
Kulak
J M
JM
Department of Biology, University of Utah, Salt Lake City, Utah, 84112, USA.
Nguyen
T A
TA
Olivera
B M
BM
McIntosh
J M
JM
D000818:Animals; D020916:Conotoxins; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008978:Mollusk Venoms / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects*; D014793:Visual Cortex / Q000187:drug effects*
D020916:Conotoxins; D008978:Mollusk Venoms; D010455:Peptides; C098872:alpha-conotoxin MII; D009538:Nicotine; D004298:Dopamine