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J. Biol. Chem., Vol. 282, Issue 51, 36905-36913, December 21, 2007

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Novel Conantokins from Conus parius Venom Are Specific Antagonists of N-Methyl-D-aspartate Receptors^*

Russell W. Teichert¹, Elsie C. Jimenez, Vernon Twede, Maren Watkins^¶, Michael Hollmann^||, Grzegorz Bulaj^**, and Baldomero M. Olivera

From the Departments of Biology, ^¶Pathology, and ^**Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, the Department of Physical Sciences, College of Science, University of the Philippines Baguio, Baguio City 2600, Philippines, and the ^||Department of Biochemistry I-Receptor Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, D-44780 Bochum, Germany

We report the discovery and characterization of three conantokin peptides from the venom of Conus parius. Each peptide (conantokin-Pr1, -Pr2, and -Pr3) contains 19 amino acids with three -carboxyglutamate (Gla) residues, a post-translationally modified amino acid characteristic of conantokins. The new peptides contain several amino acid residues that differ from previous conantokin consensus sequences. Notably, the new conantokins lack Gla at the 3rd position from the N terminus, where the Gla residue is replaced by either aspartate or by another post-translationally modified residue, 4-trans-hydroxyproline. Conantokin-Pr3 is the first conantokin peptide to have three different post-translational modifications. Conantokins-Pr1 and -Pr2 adopt -helical conformations in the presence of divalent cations (Mg²⁺ and Ca²⁺) but are generally unstructured in the absence of divalent cations. Conantokin-Pr3 adopts an -helical conformation even in the absence of divalent cations. Like other conantokins, the new peptides induced sleep in young mice and hyperactivity in older mice upon intracranial injection. Electrophysiological assays confirmed that conantokins-Pr1, -Pr2, and -Pr3 are N-methyl-D-aspartate (NMDA) receptor antagonists, with highest potency for NR2B-containing NMDA receptors. Conantokin-Pr3 demonstrated 10-fold selectivity for NR2B-containing NMDA receptors. However, conantokin-Pr2 showed minimal differences in potency between NR2B and NR2D. Conantokins-Pr1, -Pr2, and -Pr3 all demonstrated high specificity of block for NMDA receptors, when tested against various ligand-gated ion channels. Conus parius conantokins allow for a better definition of structural and functional features of conantokins as ligands targeting NMDA receptors.

Received for publication, August 9, 2007 , and in revised form, October 17, 2007.

^* This work was supported by NIGM Program Project Grant GM48677 from National Institutes of Health. 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.

¹ To whom correspondence should be addressed: 257 S. 1400 E., Salt Lake City, UT 84112-0840. Tel.: 801-581-8370; Fax: 801-585-5010; E-mail: russ_teichert{at}yahoo.com.

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