title: Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder.
abstract: 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.
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: John W
authors.initials: JW
authors.lastname: Scott
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Core Facility, Duke University Medical Center, Durham, NC 27710.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Core Facility, Duke University Medical Center, Durham, NC 27710.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Oakhill
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: Samah M A
authors.initials: SM
authors.lastname: Issa
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: O'Brien
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: Toby A
authors.initials: TA
authors.lastname: Dite
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Langendorf
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Core Facility, Duke University Medical Center, Durham, NC 27710.|Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D013216:Reflex, Startle / Q000502:physiology; D016415:Sequence Alignment
chemical_list: D015759:Ionomycin; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D002118:Calcium