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α-Conotoxin AuIB Selectively Blocks α3β4 Nicotinic Acetylcholine Receptors and Nicotine-Evoked Norepinephrine Release

1998; Society for Neuroscience; Volume: 18; Issue: 21 Linguagem: Inglês

10.1523/jneurosci.18-21-08571.1998

1529-2401

Siqin Luo, Jennifer M. Kulak, G. Edward Cartier, Richard B. Jacobsen, Doju Yoshikami, Baldomero M. Olivera, J. Michael McIntosh,

Neurotransmitter Receptor Influence on Behavior

Neuronal nicotinic acetylcholine receptors (nAChRs) with putative α3β4-subunits have been implicated in the mediation of signaling in various systems, including ganglionic transmission peripherally and nicotine-evoked neurotransmitter release centrally. However, progress in the characterization of these receptors has been hampered by a lack of α3β4-selective ligands. In this report, we describe the purification and characterization of an α3β4 nAChR antagonist, α-conotoxin AuIB, from the venom of the “court cone,” Conus aulicus. We also describe the total chemical synthesis of this and two related peptides that were also isolated from the venom. α-Conotoxin AuIB blocks α3β4 nAChRs expressed in Xenopus oocytes with an IC 50 of 0.75 μ m , a k on of 1.4 × 10 6 min -1 m −1 , a k off of 0.48 min -1 , and a K d of 0.5 μ m . Furthermore, α-conotoxin AuIB blocks the α3β4 receptor with >100-fold higher potency than other receptor subunit combinations, including α2β2, α2β4, α3β2, α4β2, α4β4, and α1β1γδ. Thus, AuIB is a novel, selective probe for α3β4 nAChRs. AuIB (1–5 μ m ) blocks 20–35% of the nicotine-stimulated norepinephrine release from rat hippocampal synaptosomes, whereas nicotine-evoked dopamine release from striatal synaptosomes is not affected. Conversely, the α3β2-specific α-conotoxin MII (100 n m ) blocks 33% of striatal dopamine release but not hippocampal norepinephrine release. This suggests that in the respective systems, α3β4-containing nAChRs mediate norepinephrine release, whereas α3β2-containing receptors mediate dopamine release.