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The Journal of Neuroscience, January 19, 2005, 25(3):732-736; doi:10.1523/JNEUROSCI.4065-04.2005

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BRIEF COMMUNICATION
A Uniquely Selective Inhibitor of the Mammalian Fetal Neuromuscular Nicotinic Acetylcholine Receptor

Russell W. Teichert,¹ Jean Rivier,² Josep Torres,² John Dykert,² Charleen Miller,² and Baldomero M. Olivera¹

¹Department of Biology, University of Utah, Salt lake City, Utah 84112, and ²Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037

We have purified and characterized a novel conotoxin from the venom of Conus obscurus, which has the unique property of selectively and potently inhibiting the fetal form of the mammalian neuromuscular nicotinic acetylcholine receptor (nAChR) (11-subunits). Although this conotoxin, A-conotoxin OIVB (A-OIVB), is a high-affinity antagonist (IC₅₀ of 56 nM) of the fetal muscle nAChR, it has >1800-fold lower affinity for the adult muscle nAChR (11-subunits) and virtually no inhibitory activity at a high concentration on various neuronal nAChRs (IC₅₀ > 100 µM in all cases). The peptide (amino acid sequence, CCGVONAACPOCVCNKTCG), with three disulfide bonds, has been chemically synthesized in a biologically active form. Although the neuromuscular nAChRs are perhaps the most extensively characterized of the receptors/ion channels of the nervous system, the precise physiological roles of the fetal form of the muscle nAChR are essentially unknown.A-OIVB is a potentially important tool for delineating the functional roles of11 receptors in normal development, as well as in various adult tissues and in pathological states. In addition to its potential as a research tool, A-OIVB may have some direct biomedical applications.

View larger version (30K): [in this window] [in a new window]   Figure 1. Purification of A-OIVB. A, Milked venom was fractionated on a reversed-phase C8 HPLC column. B, Further purification of the fraction marked by an arrow in A providedA-OIVB as the major peak, also marked by an arrow in B.

 

View larger version (14K): [in this window] [in a new window]   Figure 2. Comigration of synthetic and native A-OIVB using CZE (100 mM Na2HPO4 buffer at pH 2.5 and a voltage of 15 kV). AUFS, Absorbance units full scale.

 

Key words: fetal; muscle; nAChR; acetylcholine; inhibitor; receptor

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Received Sep 30, 2004; revised November 15, 2004; accepted November 16, 2004.

This article has been cited by other articles:

				Y. Liu, D. Padgett, M. Takahashi, H. Li, A. Sayeed, R. W. Teichert, B. M. Olivera, J. J. McArdle, W. N. Green, and W. Lin Essential roles of the acetylcholine receptor {gamma}-subunit in neuromuscular synaptic patterning Development, June 1, 2008; 135(11): 1957 - 1967. [Abstract] [Full Text] [PDF]

				B. M. Olivera and R. W. Teichert Diversity of the Neurotoxic Conus Peptides: A Model for Concerted Pharmacological Discovery Mol. Interv., October 1, 2007; 7(5): 251 - 260. [Abstract] [Full Text] [PDF]

				X. Wang, K. L. Engisch, R. W. Teichert, B. M. Olivera, M. J. Pinter, and M. M. Rich Prolongation of Evoked and Spontaneous Synaptic Currents at the Neuromuscular Junction after Activity Blockade Is Caused by the Upregulation of Fetal Acetylcholine Receptors. J. Neurosci., August 30, 2006; 26(35): 8983 - 8987. [Abstract] [Full Text] [PDF]

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