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J. Biol. Chem., Vol. 280, Issue 26, 25258-25266, July 1, 2005

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Pituitary Adenylyl Cyclase-activating Polypeptide 38 Reduces Astroglial Proliferation by Inhibiting the GTPase RhoA^*

Dieter K. Meyer, Catharina Fischer, Ulrike Becker, Isabel Göttsching, Stephanie Boutillier, Christian Baermann, Gudula Schmidt, Norbert Klugbauer, and Jost Leemhuis

From the Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Zentrum für Neurowissenschaften, Albert-Ludwigs-Universität, D-79104 Freiburg, Germany

Pituitary adenylyl cyclase-activating polypeptide 38 (PACAP38) plays an important role in the proliferation and differentiation of neural cells. In the present study, we have investigated how PACAP38 inhibits the proliferation of cultured neocortical astroglial cells. When applied to synchronized cells during the G₁ phase of the cell cycle, PACAP38 diminished the subsequent nuclear uptake of bromodeoxyuridine. When applied for 2 days, it reduced the cell number. PACAP38 did not exert its antiproliferative effect by activating protein kinase A. It also did not reduce the activity of mitogen-activated protein kinases essential for G₁ phase progression. Instead, PACAP38 acted on a member of the Rho family of small GTPases. It reduced the activity of RhoA as was shown with a Rhotekin pull-down assay. The decrease in endogenous RhoA activity induced by treatment of the cells with C3 exotoxin or by expression of dominant negative RhoA also reduced the nuclear uptake of bromodeoxyuridine. In contrast, expression of constitutively active RhoA prevented the effect of PACAP38. Our data show a novel signal transduction pathway by which the neuropeptide influences cell proliferation.

Received for publication, February 11, 2005 , and in revised form, April 1, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 505/B6; Grako 483 (to C. F.). 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: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albert-Str. 25, D-79104 Freiburg, Germany. Tel.: 49-761-2035327; Fax: 49-761-2035326; E-mail: dieter.meyer{at}pharmakol.uni-freiburg.de.

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