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

Publication ,  Journal Article
Scott, JW; Park, E; Rodriguiz, RM; Oakhill, JS; Issa, SMA; O'Brien, MT; Dite, TA; Langendorf, CG; Wetsel, WC; Means, AR; Kemp, BE
Published in: Sci Rep
September 23, 2015

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.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

September 23, 2015

Volume

5

Start / End Page

14436

Location

England

Related Subject Headings

  • Sequence Alignment
  • Reflex, Startle
  • Phosphorylation
  • Mutation
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Maze Learning
  • Lithium Chloride
  • Ionomycin
 

Citation

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Scott, J. W., Park, E., Rodriguiz, R. M., Oakhill, J. S., Issa, S. M. A., O’Brien, M. T., … Kemp, B. E. (2015). Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Sci Rep, 5, 14436. https://doi.org/10.1038/srep14436
Scott, John W., Elizabeth Park, Ramona M. Rodriguiz, Jonathan S. Oakhill, Samah M. A. Issa, Matthew T. O’Brien, Toby A. Dite, et al. “Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder.Sci Rep 5 (September 23, 2015): 14436. https://doi.org/10.1038/srep14436.
Scott JW, Park E, Rodriguiz RM, Oakhill JS, Issa SMA, O’Brien MT, et al. Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Sci Rep. 2015 Sep 23;5:14436.
Scott, John W., et al. “Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder.Sci Rep, vol. 5, Sept. 2015, p. 14436. Pubmed, doi:10.1038/srep14436.
Scott JW, Park E, Rodriguiz RM, Oakhill JS, Issa SMA, O’Brien MT, Dite TA, Langendorf CG, Wetsel WC, Means AR, Kemp BE. Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Sci Rep. 2015 Sep 23;5:14436.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

September 23, 2015

Volume

5

Start / End Page

14436

Location

England

Related Subject Headings

  • Sequence Alignment
  • Reflex, Startle
  • Phosphorylation
  • Mutation
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Maze Learning
  • Lithium Chloride
  • Ionomycin