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J. Biol. Chem., Vol. 282, Issue 14, 10506-10515, April 6, 2007

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Neural Expression of G Protein-coupled Receptors GPR3, GPR6, and GPR12 Up-regulates Cyclic AMP Levels and Promotes Neurite Outgrowth^*

Shigeru Tanaka, Ken Ishii, Kazue Kasai, Sung Ok Yoon^¶, and Yoshinaga Saeki¹

From the Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, ^¶Department of Molecular and Cellular Biochemistry, and Center for Molecular Neurobiology, the Ohio State University, Columbus, Ohio 43210 and the Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan

Cyclic AMP regulates multiple neuronal functions, including neurite outgrowth and axonal regeneration. GPR3, GPR6, and GPR12 make up a family of constitutively active G protein-coupled receptors (GPCRs) that share greater than 50% identity and 65% similarity at the amino acid level. They are highly expressed in the central nervous system, and their expression in various cell lines results in constitutive stimulation of cAMP production. When the constitutively active GPCRs were overexpressed in rat cerebellar granule neurons in culture, the transfected neurons exhibited significantly enhanced neurite outgrowth and overcame growth inhibition caused by myelin-associated glycoprotein. GPR12-mediated neurite outgrowth was the most prominent and was shown to depend on G_s and cAMP-dependent protein kinase. Moreover, the GPR12-mediated rescue from myelin-associated glycoprotein inhibition was attributable to cAMP-dependent protein kinase-mediated inhibition of the small GTPase, RhoA. Among the three receptors, GPR3 was revealed to be enriched in the developing rat cerebellar granule neurons. When the endogenous GPR3 was knocked down, significant reduction of neurite growth was observed, which was reversed by expression of either GPR3 or GPR12. Taken together, our results indicate that expression of the constitutively active GPCRs up-regulates cAMP production in neurons, stimulates neurite outgrowth, and counteracts myelin inhibition. Further characterization of the GPCRs in developing and injured mammalian neurons should provide insights into how basal cAMP levels are regulated in neurons and could establish a firm scientific foundation for applying receptor biology to treatment of various neurological disorders.

Received for publication, January 31, 2007

^* This work was supported by National Institutes of Health Grant R21 NS44514 (to Y. S.), the Gerlach Foundation, and the Dardinger Center Fund for Neuro-oncology Research at the Arthur G. James Cancer Hospital, Ohio State University Medical Center. 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 movies 1 and 2.

¹ To whom correspondence should be addressed: Dardinger Laboratory for Neuro-oncology and Neurosciences, Dept. of Neurological Surgery, Ohio State University Medical Center, 385B Wiseman Hall-CCC, 400 West 12th Ave., Columbus, OH 43210. Tel.: 614-292-3804; Fax: 614-688-4882; E-mail: saeki.6{at}osu.edu.

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