(+)‐Anatoxin‐a Is a Potent Agonist at Neuronal Nicotinic Acetylcholine Receptors

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Abstract
The effects of the nicotinic agonist (+)‐anatoxin‐a have been examined in four different preparations, representing at least two classes of neuronal nicotinic receptors. (+)‐Anatoxin‐a was most potent (EC50= 48 nM) in stimulating 86Rb+ influx into M10 cells, which express the nicotinic receptor subtype comprising α4 and β2 subunits. A presynaptic nicotinic receptor mediating acetylcholine release from hippocampal synaptosomes was similarly sensitive to (+)‐anatoxin‐a (EC50= 140 nM). α‐Bungarotoxin‐sensitive neuronal nicotinic receptors, studied using patch‐clamp recording techniques, required slightly higher concentrations of this alkaloid for activation: Nicotinic currents in hippocampal neurons were activated by (+)‐anatoxin‐a with an EC50 of 3.9 γM, whereas α7 homooligomers reconstituted in Xenopus oocytes yielded an EC50 value of 0.58 γM for (+)‐anatoxin‐a. In these diverse preparations, (+)‐anatoxin‐a was between three and 50 times more potent than (–)‐nicotine and ˜20 times more potent than acetylcholine, making it the most efficacious nicotinic agonist thus far described.