Scientific reports, 2015-09, Vol.5 (1), p.14436-14436, Article 14436
2015
Details
- Autor(en) / Beteiligte
- Titel
- Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder
- Ist Teil von
- Scientific reports, 2015-09, Vol.5 (1), p.14436-14436, Article 14436
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2015
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Mutations that reduce expression or give rise to a Thr85Ser (T85S) mutation of Ca(2+)-CaM-dependent protein kinase kinase-2 (CaMKK2) have been implicated in behavioural disorders such as anxiety, bipolar and schizophrenia in humans. Here we report that Thr85 is an autophosphorylation site that endows CaMKK2 with a molecular memory that enables sustained autonomous activation following an initial, transient Ca(2+) signal. Conversely, autophosphorylation of Ser85 in the T85S mutant fails to generate autonomous activity but instead causes a partial loss of CaMKK2 activity. The loss of autonomous activity in the mutant can be rescued by blocking glycogen synthase kinase-3 (GSK3) phosphorylation of CaMKK2 with the anti-mania drug lithium. Furthermore, CaMKK2 null mice representing a loss of function model the human behavioural phenotypes, displaying anxiety and manic-like behavioural disturbances. Our data provide a novel insight into CaMKK2 regulation and its perturbation by a mutation associated with behavioural disorders.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/srep14436Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4585769
- Format
- –
- Schlagworte
- Affective disorders, Amino Acid Sequence, Animals, Anxiety, Anxiety - genetics, Bipolar disorder, Bipolar Disorder - genetics, Calcium - metabolism, Calcium signalling, Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics, Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism, Cell Line, Cercopithecus aethiops, COS Cells, Glycogen, Glycogen synthase kinase 3, Glycogen Synthase Kinase 3 - antagonists & inhibitors, Humans, Ionomycin - pharmacology, Kinases, Lithium, Lithium Chloride - pharmacology, Maze Learning - physiology, Mental disorders, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Mutation - genetics, Phosphorylation, Protein kinase, Reflex, Startle - physiology, Schizophrenia, Sequence Alignment