title: Differential control of presynaptic CaMKII activation and translocation to active zones.
abstract: The release of neurotransmitters, neurotrophins, and neuropeptides is modulated by Ca(2+) mobilization from the endoplasmic reticulum (ER) and activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Furthermore, when neuronal cultures are subjected to prolonged depolarization, presynaptic CaMKII redistributes from the cytoplasm to accumulate near active zones (AZs), a process that is reminiscent of CaMKII translocation to the postsynaptic side of the synapse. However, it is not known how presynaptic CaMKII activation and translocation depend on neuronal activity and ER Ca(2+) release. Here these issues are addressed in Drosophila motoneuron terminals by imaging a fluorescent reporter of CaMKII activity and subcellular distribution. We report that neuronal excitation acts with ER Ca(2+) stores to induce CaMKII activation and translocation to a subset of AZs. Surprisingly, activation is slow, reflecting T286 autophosphorylation and the function of presynaptic ER ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs). Furthermore, translocation is not simply proportional to CaMKII activity, as T286 autophosphorylation promotes activation, but does not affect translocation. In contrast, RNA interference-induced knockdown of the AZ scaffold protein Bruchpilot disrupts CaMKII translocation without affecting activation. Finally, RyRs comparably stimulate both activation and translocation, but IP3Rs preferentially promote translocation. Thus, Ca(2+) provided by different presynaptic ER Ca(2+) release channels is not equivalent. These results suggest that presynaptic CaMKII activation depends on autophosphorylation and global Ca(2+) in the terminal, while translocation to AZs requires Ca(2+) microdomains generated by IP3Rs.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Dinara
authors.initials: D
authors.lastname: Shakiryanova
authors.forename: Takako
authors.initials: T
authors.lastname: Morimoto
authors.forename: Chaoming
authors.initials: C
authors.lastname: Zhou
authors.forename: Amit K
authors.initials: AK
authors.lastname: Chouhan
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
authors.forename: Akinao
authors.initials: A
authors.lastname: Nose
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Macleod
authors.forename: David L
authors.initials: DL
authors.lastname: Deitcher
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Levitan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D004330:Drosophila / Q000378:metabolism*; D004789:Enzyme Activation; D025461:Feedback, Physiological / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D021381:Protein Transport; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium