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J. Biol. Chem., Vol. 283, Issue 46, 31949-31959, November 14, 2008

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Neuronostatin Encoded by the Somatostatin Gene Regulates Neuronal, Cardiovascular, and Metabolic Functions^*

Willis K. Samson¹², Jian V. Zhang¹, Orna Avsian-Kretchmer, Kai Cui^¶, Gina L. C. Yosten, Cindy Klein, Rong-Ming Lyu^||, Yong Xiong Wang^||, Xiang Qun Chen^||, Jun Yang^||, Christopher J. Price^**, Ted D. Hoyda^**, Alastair V. Ferguson^**, Xiao-bin Yuan^¶, Jaw Kang Chang^||, and Aaron J. W. Hsueh³

From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, the Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305, the ^¶Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, ^||Phoenix Pharmaceuticals Inc., Burlingame, California 94010, and the ^**Department of Physiology, Queen's University, Botterell Hall, Kingston, Ontario K7L 3N6, Canada

Somatostatin is important in the regulation of diverse neuroendocrine functions. Based on bioinformatic analyses of evolutionarily conserved sequences, we predicted another peptide hormone in pro-somatostatin and named it neuronostatin. Immuno-affinity purification allowed the sequencing of an amidated neuronostatin peptide of 13 residues from porcine tissues. In vivo treatment with neuronostatin induced c-Fos expression in gastrointestinal tissues, anterior pituitary, cerebellum, and hippocampus. In vitro treatment with neuronostatin promoted the migration of cerebellar granule cells and elicited direct depolarizing actions on paraventricular neurons in hypothalamic slices. In a gastric tumor cell line, neuronostatin induced c-Fos expression, stimulated SRE reporter activity, and promoted cell proliferation. Furthermore, intracerebroventricular treatment with neuronostatin increased blood pressure but suppressed food intake and water drinking. Our findings demonstrate diverse neuronal, neuroendocrine, and cardiovascular actions of a somatostatin gene-encoded hormone and provide the basis to investigate the physiological roles of this endogenously produced brain/gut peptide.

Received for publication, June 23, 2008 , and in revised form, August 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL68652 (to W. K. S.) and HL66023 (to W. K. S. and A. V. F.). This work was also supported by Johnson & Johnson Pharmaceutical Research & Development, L.L.C (to A. J. H.), and a grant from the Shanghai Institutes of Biological Sciences (to X. B. Y.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S2, S10, and S11.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: samsonwk{at}slu.edu.

³ To whom correspondence may be addressed. E-mail: aaron.hsueh{at}stanford.edu.

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