Calmodulin Controls Synaptic Strength via Presynaptic Activation of Calmodulin Kinase II

Abstract

Calmodulin regulates multifarious cellular processes via a panoply of target interactions. However, the central role, multiple isoforms, and complex target interactions of calmodulin make it difficult to examine its precise functions. Here, we analyzed calmodulin function in neurons using lentivirally delivered short-hairpin RNAs that suppressed expression of all calmodulin isoforms by ϳ70%. Calmodulin knockdown did not significantly alter neuronal survival or synapse formation but depressed spontaneous neuronal network activity. Strikingly, calmodulin knockdown decreased the presynaptic release probability almost twofold, without altering the presynaptic readily-releasable vesicle pool or postsynaptic neurotransmitter reception. In calmodulin knockdown neurons, presynaptic release was restored to wild-type levels by expression of constitutively active calmodulin-dependent kinase-II␣ (CaMKII␣); in contrast, in control neurons, expression of constitutively active CaMKII␣ had no effect on presynaptic release. Viewed together, these data suggest that calmodulin performs a major function in boosting synaptic strength via direct activation of presynaptic calmodulin-dependent kinase II.

Constitutive Activation of Ca2+/Calmodulin-Dependent Protein Kinase II during Development Impairs Central Cholinergic Transmission in a Circuit Underlying Escape Behavior inDrosophila

“…In contrast, presynaptic expression of CaMKII-T287D in cholinergic chordotonal (sensory) neurons eliminates habituation of a reflex controlling the leg position (Jin et al, 1998), while at the larval glutamatergic NMJs, presynaptic expression in the motoneurons increases the number of boutons without affecting neurotransmitter release and alters potassium conductance in motoneuron axons (Koh et al, 1999;Park et al, 2002) Thus, both GFS central cholinergic and peripheral glutamatergic NMJs in the adult appear to be nonresponsive to kinase alterations. Consistent with this, a recent study provides evidence that in mammalian cultured cortical neurons, expression of constitutively active CaMKII␣ has no effect on presynaptic release (Pang et al, 2010).…”

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

“…CaMKs contribute to a number of regulatory pathways involving, for example, phosphorylation of AMPA receptors (Barria et al 1997) and the nuclear transcription factor CREB (Deisseroth et al 1998). Calmodulin also positively regulates presynaptic release probability and this is mediated via activation of CaMKII (Pang et al 2010). The Ca 2þ -activated phosphatase calcineurin can dephosphorylate a wide range of neuronal proteins, leading to direct effects and effects through changes in gene transcription following activation of the transcription factor NFAT and its translocation into the nucleus.…”

Ca2+-independent Activation of Ca2+/Calmodulin-dependent Protein Kinase II Bound to the C-terminal Domain of CaV2.1 Calcium Channels

“…Previous studies implicate presynaptic CaMKII in different forms of synaptic plasticity (25)(26)(27)(28)(29), including modulation of paired-pulse facilitation (30 -32). CaMKII forms a complex with Ca V 2.1 channels in transfected cells via a site in the proximal C-termi-nal domain (33).…”