title: Ganglioside GQ1b induces dopamine release through the activation of Pyk2.
abstract: Growing evidence indicates that GQ1b, one of the gangliosides members, contributes to synaptic transmission and synapse formation. Previous studies have shown that GQ1b could enhance depolarization induced neurotransmitter release, while the role of GQ1b in asynchronous release is still largely unknown. Here in our result, we found low concentration of GQ1b, but not GT1b or GD1b (which were generated from GQ1b by plasma membrane-associated sialidases), evoked asynchronous dopamine (DA) release from both clonal rat pheochromocytoma PC12 cells and rat striatal slices significantly. The release peaked at 2 min after GQ1b exposure, and lasted for more than 6 min. This effect was caused by the enhancement of intracellular Ca(2+) and the activation of Pyk2. Inhibition of Pyk2 by PF-431396 (a dual inhibitor of Pyk2 and FAK) or Pyk2 siRNA abolished DA release induced by GQ1b. Moreover, Pyk2 Y402, but not other tyrosine site, was phosphorylated at the peaking time. The mutant of Pyk2 Y402 (Pyk2-Y402F) was built to confirm the essential role of Y402 activation. Further studies revealed that activated Pyk2 stimulated ERK1/2 and p-38, while only the ERK1/2 activation was indispensable for GQ1b induced DA release, which interacted with Synapsin I directly and led to its phosphorylation, then depolymerization of F-actin, thus contributed to DA release. In conclusion, low concentration of GQ1b is able to enhance asynchronous DA release through Pyk2/ERK/Synapsin I/actin pathway. Our findings provide new insights into the role of GQ1b in neuronal communication, and implicate the potential application of GQ1b in neurological disorders.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.
authors.forename: Shi-Feng
authors.initials: SF
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Mou
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, China.
authors.forename: Gui-Ning
authors.initials: GN
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. Electronic address: chennh@imm.ac.cn.
authors.forename: Nai-Hong
authors.initials: NH
authors.lastname: Chen
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism; D005089:Exocytosis; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems; D016704:Synapsins / Q000378:metabolism
chemical_list: D000199:Actins; D005732:Gangliosides; D016704:Synapsins; C039129:GQ1b ganglioside; D051418:Focal Adhesion Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium; D004298:Dopamine
keywords: Dopamine; F-actin; GQ1b; MAPK/ERK; PC12; Pyk2; Synapsin I