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J. Biol. Chem., Vol. 280, Issue 34, 30107-30112, August 26, 2005

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A Novel -Conotoxin, PeIA, Cloned from Conus pergrandis, Discriminates between Rat 910 and 7 Nicotinic Cholinergic Receptors^*

J. Michael McIntosh¶, Paola V. Plazas||, Maren Watkins, María E. Gomez-Casati||, Baldomero M. Olivera**, and A. Belén Elgoyhen||

From the Departments of Psychiatry, ^**Biology, and Pathology, University of Utah, Salt Lake City, Utah 84112 and ^||Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad de Buenos Aires, Buenos Aires 1428, Argentina

The 9 and 10 nicotinic cholinergic subunits assemble to form the receptor believed to mediate synaptic transmission between efferent olivocochlear fibers and hair cells of the cochlea, one of the few examples of postsynaptic function for a non-muscle nicotinic acetylcholine receptor (nAChR). However, it has been suggested that the expression profile of 9 and 10 overlaps with that of 7 in the cochlea and in sites such as dorsal root ganglion neurons, peripheral blood lymphocytes, developing thymocytes, and skin. We now report the cloning, total synthesis, and characterization of a novel toxin -conotoxin PeIA that discriminates between 910 and 7 nAChRs. This is the first toxin to be identified from Conus pergrandis, a species found in deep waters of the Western Pacific. -Conotoxin PeIA displayed a 260-fold higher selectivity for -bungarotoxin-sensitive 910 nAChRs compared with -bungarotoxin-sensitive 7 receptors. The IC₅₀ of the toxin was 6.9 ± 0.5 nM and 4.4 ± 0.5 nM for recombinant 910 and wild-type hair cell nAChRs, respectively. -Conotoxin PeIA bears high resemblance to -conotoxins MII and GIC isolated from Conus magus and Conus geographus, respectively. However, neither -conotoxin MII nor -conotoxin GIC at concentrations of 10 µM blocked acetylcholine responses elicited in Xenopus oocytes injected with the 9 and 10 subunits. Among neuronal non--bungarotoxin-sensitive receptors, -conotoxin PeIA was also active at 32 receptors and chimeric 6/323 receptors. -Conotoxin PeIA represents a novel probe to differentiate responses mediated either through 910 or 7 nAChRs in those tissues where both receptors are expressed.

Received for publication, April 14, 2005 , and in revised form, June 10, 2005.

^* This work was supported by National Institutes of Health MH53631 (to J. M. M.), GM48677 (to B. M. O.), and a Howard Hughes international scholar grant, Agencia Nacional de Promoción Científica y Tecnológica and Universidad de Buenos Aires, Argentina (to A. B. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112-0840. Tel.: 801-585-3622; E-mail: mcintosh.mike{at}gmail.com.

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