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J Biol Chem, Vol. 274, Issue 50, 35305-35308, December 10, 1999

COMMUNICATION
A G Protein  Subunit-specific Peptide Inhibits Muscarinic Receptor Signaling^*

Inaki Azpiazu^§, Humberto Cruzblanca^§¶, Ping Li, Maurine Linder^**, Min Zhuo, and N. Gautam

From the  Department of Anesthesiology and the ^** Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^¶ Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195

Muscarinic acetylcholine receptors modulate the function of a variety of effectors through heterotrimeric G proteins. A prenylated peptide specific to the G protein 5 subunit type inhibits G protein activation by the M2 muscarinic receptor in a reconstitution assay. Scrambling the amino acid sequence of the peptide significantly reduces the efficacy of the peptide. The peptide does not disrupt the G protein heterotrimer. In cultured sympathetic neurons, the 5 peptide inhibits modulation of Ca²⁺ current by the M4 receptor. Peptide activity is specific, the scrambled peptide and peptides specific to two other members of the G protein  subunit family are significantly less effective. The 5 peptide has no effect on Ca²⁺ current modulation by the 2-adrenergic and somatostatin receptors. In addition, the 5 peptide inhibits muscarinic receptor signaling in spinal cord slices with specificity. These results support a specific role for G protein  subunit types in signal transduction, most likely at the receptor-G protein interface.

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^* This work was supported by Consejo Nacional de Ciencia y Tecnologia Grant 4113P-N9607 and Pew Charitable trusts (to H. C.), by National Institutes of Health Grants GM51466 (to M. L.), NS08174 (to Dr. Bertil Hille), and GM46963 (to N. G.), and by the NINDS and NIDA (to M. Z.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ These two authors contributed equally to this work.

Present address: Centro Universitario de Investigaciones Biomedicas, Universidad de Colima Col. Villa San Sebastian Colima, Col. 28000, Mexico.

To whom correspondence should be addressed: Box 8054, Washington University School of Medicine, St. Louis, MO 63110. Tel.: 314-362-8568; Fax: 314-362-8571; E-mail: gautam@morpheus.wustl.edu.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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