Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates adenylyl cyclase and phospholipase C activity in rat cerebellar neuroblasts.
The presence of receptors for the novel neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been recently demonstrated in the external granule cell layer of the cerebellum, a germinative matrix that generates the majority of cerebellar interneurons. In the present study, we have taken advantage of the possibility of obtaining a culture preparation that is greatly enriched in immature cerebellar granule cells to investigate the effect of PACAP on the adenylyl cyclase and phospholipase C transduction pathways. The two molecular forms of PACAP, i.e., 27-(PACAP27) and 38-(PACAP38) amino-acid forms of PACAP, induced a dose-dependent stimulation of cyclic AMP production in granule cells. The potencies of PACAP27 and PACAP38 were similar (ED50 = 0.12 +/- 0.01 and 0.23 +/- 0.07 nM, respectively), whereas vasoactive intestinal polypeptide (VIP) was approximately 100 times less potent. PACAP27 and PACAP38 also induced a dose-dependent stimulation of polyphosphoinositide breakdown (ED50 = 19.1 +/- 6.3 and 13.4 +/- 6.0 nM, respectively), whereas VIP had no effect on polyphosphoinositide metabolism. The effect of PACAP38 on inositol phosphate formation was significantly reduced by U-73122 and by pertussis toxin, indicating that activation of PACAP receptors causes stimulation of a phospholipase C through a pertussis toxin-sensitive G protein. In contrast, forskolin and dibutyryl cyclic AMP did not affect PACAP-induced stimulation of inositol phosphates. Taken together, the present results demonstrate that PACAP stimulates independently the adenylyl cyclase and the phospholipase C transduction pathways in immature cerebellar granule cells. These data favor the concept that PACAP may play important roles in the control of proliferation and/or differentiation of cerebellar neuroblasts.
Basille
M
M
European Institute for Peptide Research (IFRMP 23), UA CNRS, University of Rouen, Mont-Saint-Aignan, France.
Gonzalez
B J
BJ
Desrues
L
L
Demas
M
M
Fournier
A
A
Vaudry
H
H
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology*; D000242:Cyclic AMP / Q000096:biosynthesis; D004963:Estrenes / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D037342:Pertussis Toxin; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C495403:Adcyap1 protein, rat; D037361:Adenylate Cyclase Toxin; D004963:Estrenes; D007295:Inositol Phosphates; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011760:Pyrrolidinones; D010566:Virulence Factors, Bordetella; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases