Background: According to current hypotheses, antidepressant drug action is the result of adaptive changes in neuronal signaling mechanisms rather than a primary effect on neurotransmitter transporters, receptors, or metabolic enzymes. Among the signaling mechanisms involved, protein kinases and phosphorylation have been shown to be modified by drug treatment. Presynaptic signaling (calcium/calmodulin-dependent protein kinase II [CaMKII]) and the protein machinery regulating transmitter release have been implicated in the action of these drugs.
Methods: We investigated the effect of S-adenosylmethionine (SAM), a compound with putative antidepressant activity, on presynaptic CaMKII and its synaptic vesicle substrate synapsin I. The activity of CaMKII was assayed in synaptic subcellular fractions prepared from hippocampus (HI), frontal cortex (FCX), striatum (STR), and parieto-temporal cortex.
Results: The kinase activity was increased after SAM treatment in the synaptic vesicle fraction of HI (31.7%), FCX (35.9%), and STR (18.4%). The protein level of CaMKII was also increased in synaptic vesicles of HI (40.4%). The synapsin I level was unchanged in synaptic vesicles but markedly increased in synaptic cytosol of HI (75.8%) and FCX (163.0%). No changes for both CaMKII and synapsin I level were found in homogenates, suggesting that synaptic protein changes are not explained by an increase in total level of proteins, but rather by translocation to nerve terminals.
Conclusions: Similar to typical antidepressant drugs, SAM induces changes in CaMKII activity and increases synapsin I level in HI and FCX nerve terminals, suggesting a modulatory action on transmitter release.
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Accepted: April 16, 2001
Received in revised form: March 14, 2001
Received: October 16, 2000
© 2001 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.