CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning.

John M Gillespie,James J L Hodge

doi:10.3389/fnmol.2013.00027

Abstract

Calcium (Ca2+)/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 (Ca2+)/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 Ca2+ 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 Ca2+ signaling observed in the CASK β null mutant caused a decrease in vesicle trafficking at synapses. In addition, the decrease in Ca2+ 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 Ca2+ signaling observed in CASK mutants to the level of wildtype, suggesting that CASK regulates Ca2+ signaling via EAG. CASK knockdown reduced both appetitive associative learning and odor evoked Ca2+ 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.

Highlights

CaMKII has been proposed to act as a molecular switch during increased neuronal activity, when increased Ca2+ levels stimulate CaMKII activity to induce the changes in synaptic strength that underlie learning
CaMKII autophosphorylation is a central mechanism in synaptic plasticity and associative memory formation in mammals and Drosophila (Giese et al, 1998; Lisman et al, 2002; Park et al, 2002; Hardingham et al, 2003; Mehren and Griffith, 2004; Hodge et al, 2006; Sanhueza et al, 2011; Malik et al, 2013)
The finding that CASK can regulate CaMKII autophosphorylation suggests that this mechanism may have a role in the cognitive deficits induced by CASK mutation in humans (Froyen et al, 2007; Najm et al, 2008; Piluso et al, 2009; Tarpey et al, 2009)

Summary

Introduction

CaMKII has been proposed to act as a molecular switch during increased neuronal activity, when increased Ca2+ levels stimulate CaMKII activity to induce the changes in synaptic strength that underlie learning. T287 autophosphorylation occurs in response to prolonged increases in Ca2+, which result in constitutively active CaMKII that is independent of Ca2+. This constitutive CaMKII activity has been suggested to be important for long-term potentiation (LTP) and memory in rodents (Giese et al, 1998; Hardingham et al, 2003; Sanhueza et al, 2011) and Drosophila (Park et al, 2002; Mehren and Griffith, 2004; Hodge et al, 2006; Malik et al, 2013). Interactions of CASK with CaMKII can lead to inhibition of CaMKII activity through CaMKII autophosphorylation at a second pair of sites, T305/T306 This process results in reduced binding of CaMKII to CaM, which decreases kinase activation by

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Conclusion