CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning.
Calcium (Ca(2+))/calmodulin (CaM)-dependent kinase II (CaMKII) activity plays a fundamental role in learning and memory. A key feature of CaMKII in memory formation is its ability to be regulated by autophosphorylation, which switches its activity on and off during synaptic plasticity. The synaptic scaffolding protein CASK (calcium (Ca(2+))/calmodulin (CaM) associated serine kinase) is also important for learning and memory, as mutations in CASK result in intellectual disability and neurological defects in humans. We show that in Drosophila larvae, CASK interacts with CaMKII to control neuronal growth and calcium signaling. Furthermore, deletion of the CaMK-like and L27 domains of CASK (CASK β null) or expression of overactive CaMKII (T287D) produced similar effects on synaptic growth and Ca(2+) signaling. CASK overexpression rescues the effects of CaMKII overactivity, consistent with the notion that CASK and CaMKII act in a common pathway that controls these neuronal processes. The reduction in Ca(2+) signaling observed in the CASK β null mutant caused a decrease in vesicle trafficking at synapses. In addition, the decrease in Ca(2+) signaling in CASK mutants was associated with an increase in Ether-à-go-go (EAG) potassium (K(+)) channel localization to synapses. Reducing EAG restored the decrease in Ca(2+) signaling observed in CASK mutants to the level of wildtype, suggesting that CASK regulates Ca(2+) signaling via EAG. CASK knockdown reduced both appetitive associative learning and odor evoked Ca(2+) responses in Drosophila mushroom bodies, which are the learning centers of Drosophila. Expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation.
School of Physiology and Pharmacology, University of Bristol Bristol, UK.
John M
JM
Gillespie
James J L
JJ
Hodge
CASK; CaMKII; Drosophila; appetitive learning; autophosphorylation; calcium imaging; synaptic function