title: Pituitary adenylate cyclase activating polypeptide modulates catecholamine storage and exocytosis in PC12 cells.
abstract: A number of efforts have been made to understand how pituitary adenylate cyclase activating polypeptide (PACAP) functions as a neurotrophic and neuroprotective factor in Parkinson's disease (PD). Recently its effects on neurotransmission and underlying mechanisms have generated interest. In the present study, we investigate the effects of PACAP on catecholamine storage and secretion in PC12 cells with amperometry and transmission electron microscopy (TEM). PACAP increases quantal release induced by high K+ without significantly regulating the frequency of vesicle fusion events. TEM data indicate that the increased volume of the vesicle is mainly the result of enlargement of the fluidic space around the dense core. Moreover, the number of docked vesicles isn't modulated by PACAP. When cells are acutely treated with L-DOPA, the vesicular volume and quantal release both increase dramatically. It is likely that the characteristics of amperometric spikes from L-DOPA treated cells are associated with increased volume of individual vesicles rather than a direct effect on the mechanics of exocytosis. Treatment with PACAP versus L-DOPA results in different profiles of the dynamics of exocytosis. Release via the fusion pore prior to full exocytosis was observed with the same frequency following treatment with PACAP and L-DOPA. However, release events have a shorter duration and higher average current after PACAP treatment compared to L-DOPA. Furthermore, PACAP reduced the proportion of spikes having rapid decay time and shortened the decay time of both fast and slow spikes. In contrast, the distributions of the amperometric spike decay for both fast and slow spikes were shifted to longer time following L-DOPA treatment. Compared to L-DOPA, PACAP may produce multiple favorable effects on dopaminergic neurons, including protecting dopaminergic neurons against neurodegeneration and potentially regulating dopamine storage and release, making it a promising therapeutic agent for the treatment of PD.
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Gang
authors.initials: G
authors.lastname: Ning
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, United States of America; Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Department of Chemistry, University of Gothenburg, Göteborg, Sweden.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Ewing
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, United States of America; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Heien
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects*; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D046529:Microscopy, Electron, Transmission; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D002395:Catecholamines; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D004295:Dihydroxyphenylalanine