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J. Biol. Chem., Vol. 278, Issue 27, 24994-25000, July 4, 2003

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Localization of the Calcitonin Gene-related Peptide Receptor Complex at the Vertebrate Neuromuscular Junction and Its Role in Regulating Acetylcholinesterase Expression^*

Susana G. Rossi , Ian M. Dickerson  ¶ and Richard L. Rotundo  ¶ ||

From the Departments of Cell Biology and Anatomy and Physiology and Biophysics and the ^¶Neuroscience Program, University of Miami School of Medicine, Miami, Florida 33101

The calcitonin gene-related peptide (CGRP) is released by motor neurons where it exerts both short and long term effects on skeletal muscle fibers. In addition, sensory neurons release CGRP on the surrounding vasculature where it is in part responsible for local vasodilation following muscle contraction. Although CGRP-binding sites have been demonstrated in whole muscle tissue, the type of CGRP receptor and its associated proteins or its cellular localization within the tissue have not been described. Here we show that the CGRP-binding protein referred to as the calcitonin receptor-like receptor is highly concentrated at the avian neuromuscular junction together with its two accessory proteins, receptor activity modifying protein 1 and CGRP-receptor component protein, required for ligand specificity and signal transduction. Using tissue-cultured skeletal muscle we show that CGRP stimulates an increase in intracellular cAMP that in turn initiates down-regulation of acetylcholinesterase expression at the transcriptional level, and, more specifically, inhibits expression of the synaptically localized collagen-tailed form of the enzyme. Together, these studies suggest a specific role for CGRP released by spinal cord motoneurons in modulating synaptic transmission at the neuromuscular junction by locally inhibiting the expression of acetylcholinesterase, the enzyme responsible for terminating acetylcholine neurotransmission.

Received for publication, November 7, 2002 , and in revised form, April 8, 2003.

^* This work was supported by National Institutes of Health Grants AG05917 (to R. L. R.) and DK052328 (to I. M. D.) and by funds from the Muscular Dystrophy Association of America (to R. L. R.). 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. of Cell Biology and Anatomy (R-124), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. E-mail: rrotundo{at}miami.edu.

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