Chronic antidepressants induce redistribution and differential activation of alphaCaM kinase II between presynaptic compartments.
Changes in synaptic plasticity are involved in pathophysiology of depression and in the mechanism of antidepressants. Ca(2+)/calmodulin (CaM) kinase II, a protein kinase involved in synaptic plasticity, has been previously shown to be a target of antidepressants. We previously found that antidepressants activate the kinase in hippocampal neuronal cell bodies by increasing phosphorylation at Thr(286), reduce the kinase phosphorylation in synaptic membranes, and in turn its phosphorylation-dependent interaction with syntaxin-1 and the release of glutamate from hippocampal synaptosomes. Here, we investigated the chronic effect of different antidepressants (fluoxetine, desipramine, and reboxetine) on the expression and function of the kinase in distinct subcellular compartments in order to dissect the different kinase pools affected. Acute treatments did not induce any change in the kinase. In total tissue extracts chronic drug treatments induced activation of the kinase; in hippocampus (HC), but not in prefrontal/frontal cortex, this was partially accounted for by increased Thr(286) phosphorylation, suggesting the involvement of different mechanisms of activation. In synaptosomes, all drugs reduced the kinase phosphorylation, particularly in HC where, upon fractionation of the synaptosomal particulate into synaptic vesicles and membranes, we found that the drugs induced a redistribution and differential activation of the kinase between membranes and vesicles. Furthermore, a large decrease in the level and phosphorylation of synapsin I located at synaptic membranes was consistent with the observed decrease of CaM kinase II. Overall, antidepressants induce a complex pattern of modifications in distinct subcellular compartments; at presynaptic level, these changes are in line with a dampening of glutamate release.
Barbiero
Valentina S
VS
Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, Center of Neuropharmacology, University of Milano, Milano, Italy.
Giambelli
Roberto
R
Musazzi
Laura
L
Tiraboschi
Ettore
E
Tardito
Daniela
D
Perez
Jorge
J
Drago
Filippo
F
Racagni
Giorgio
G
Popoli
Maurizio
M
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000648:ultrastructure; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects; D016708:Synaptophysin / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000201:enzymology*
D000928:Antidepressive Agents; D015820:Cadherins; D016708:Synaptophysin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010751:Phosphopyruvate Hydratase