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

作者：Scott John W^*; Park Elizabeth; Rodriguiz Ramona M; Oakhill Jonathan S; Issa Samah M A; O'Brien Matthew T; Dite Toby A; Langendorf Christopher G; Wetsel William C; Means Anthony R; Kemp Bruce E

来源：Scientific Reports, 2015, 5(1): 14436.

DOI：10.1038/srep14436

Mutations that reduce expression or give rise to a Thr85Ser (T85S) mutation of Ca2+-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 Ca2+ 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.

• 出版日期2015-9-23