Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder

John W. Scott, Elizabeth Park, Ramona M. Rodriguiz, Jonathan S. Oakhill, Samah M.A. Issa, Matthew T. Obrien, Toby A. Dite, Christopher G. Langendorf, William C. Wetsel, Anthony R. Means, Bruce E. Kemp

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25 Citations (Scopus)

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.

Original languageEnglish
Article number14436
Number of pages10
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 23 Sept 2015
Externally publishedYes

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