title: Role of calcineurin in Ca2+-induced release of catecholamines and neuropeptides.
abstract: Neurotransmission requires rapid docking, fusion, and recycling of neurotransmitter vesicles. Several of the proteins involved in this complex Ca2+-regulated mechanism have been identified as substrates for protein kinases and phosphatases, e.g., the synapsins, synaptotagmin, rabphilin3A, synaptobrevin, munc18, MARCKS, dynamin I, and B-50/GAP-43. So far most attention has focused on the role of kinases in the release processes, but recent evidence indicates that phosphatases may be as important. Therefore, we investigated the role of the Ca2+/calmodulin-dependent protein phosphatase calcineurin in exocytosis and subsequent vesicle recycling. Calcineurin-neutralizing antibodies, which blocked dynamin I dephosphorylation by endogenous synaptosomal calcineurin activity, but had no effect on the activity of protein phosphatases 1 or 2A, were introduced into rat permeabilized nerve terminals and inhibited Ca2+-induced release of [3H]noradrenaline and neuropeptide cholecystokinin-8 in a specific and concentration-dependent manner. Our data show that the Ca2+/calmodulin-dependent phosphatase calcineurin plays an essential role in exocytosis and/or vesicle recycling of noradrenaline and cholecystokinin-8, transmitters stored in large dense-cored vesicles.
authors.affiliation: Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hens
authors.forename: M
authors.initials: M
authors.lastname: De Wit
authors.forename: W E
authors.initials: WE
authors.lastname: Ghijsen
authors.forename: A G
authors.initials: AG
authors.lastname: Leenders
authors.forename: H W
authors.initials: HW
authors.lastname: Boddeke
authors.forename: R
authors.initials: R
authors.lastname: Kissmehl
authors.forename: V M
authors.initials: VM
authors.lastname: Wiegant
authors.forename: U
authors.initials: U
authors.lastname: Weller
authors.forename: W H
authors.initials: WH
authors.lastname: Gispen
authors.forename: P N
authors.initials: PN
authors.lastname: De Graan
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D019703:Calcineurin / Q000276:immunology / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012844:Sincalide / Q000378:metabolism*; D013301:Streptolysins / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D013301:Streptolysins; C025964:streptolysin O; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; D012844:Sincalide; D002118:Calcium; D009638:Norepinephrine