PACAP Stimulates Biosynthesis and Release of Endozepines from Rat Astrocytes OLFA MASMOUDI-KOUKI, a,b PIERRICK GANDOLFO, a JEROME LEPRINCE, a DAVID VAUDRY, a GEORGES PELLETIER, c ALAIN FOURNIER, d HUBERT VAUDRY, a AND MARIE-CHRISTINE TONON a a Inserm U413, IFRMP23, University of Rouen, 76821 Mont-Saint-Aignan, France b 00/UR/08/01, University of Tunis, 2092 El Manar, Tunisia c CHUL Research Center, Laval University Medical Center, Quebec, G1V 4G2 Canada d INRS-Institut Armand-Frappier, Pointe-Claire, H9R1G6 Canada ABSTRACT: Astrocytes synthesize and release endozepines, a family of neuropeptides related to diazepam-binding inhibitor (DBI). Astroglial cells also express the receptors of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). In the present article, we show that PACAP dose dependently increases DBI gene expression and stimulates endozepine release through activation of PAC1-R. PACAP increases cAMP formation, enhances polyphospho- inositide turnover, and evokes calcium mobilization from intracellular Ca 2+ pools. The effect of PACAP on endozepine release is mediated through the adenylyl cyclase/PKA pathway while the downregulation of astrocyte response to PACAP can be ascribed to activation of the PLC/ PKC pathway. KEYWORDS: astrocytes; endozepines; DBI mRNA INTRODUCTION The term endozepines designates a family of regulatory peptides that have been initially isolated from the rat brain on the basis of their ability to dis- place the binding of benzodiazepines from their receptors. 1 All endozepines characterized so far derive from an 86-amino acid precursor called diazepam- binding inhibitor (DBI) which generates, through proteolytic cleavage, several Address for correspondence: Dr. Hubert Vaudry, Inserm U413, IFRMP 23, University of Rouen, 76821 Mont-Saint-Aignan, France. Voice: 33-235-14-6624; fax: 33-235-14-6946. e-mail: hubert.vaudry@univ-rouen.fr Ann. N.Y. Acad. Sci. 1070: 411–416 (2006). C  2006 New York Academy of Sciences. doi: 10.1196/annals.1317.094 411