Long-term treatment with S-adenosylmethionine induces changes in presynaptic CaM kinase II and synapsin I

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 phos phorylation have been shown to be modified by drug treatment. Presynaptic s ignaling (calcium/calmodulin-dependent protein kinase II [CaMKII])) and the protein machinery regulating transmitter release have been implicated in t he action of these drugs. Methods: We investigated the effect of S-adenosylmethionine (SAM), a compou nd with putative antidepressant activity, on presynaptic CaMKII and its syn aptic vesicle substrate synapsin I The activity of CaMKII was assayed in sy naptic 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 synap tic vesicle fraction of HI (31.7%), FCX (35.9%), and STR (18.4%). The prote in level of CaMKII was also increased in synaptic vesicles of HI (40.4%). T he synapsin I level was unchanged in synaptic vesicles but markedly increas ed 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 syna ptic protein changes are not explained by an increase in total level of pro teins, but rather by translocation to nerve terminals. Conclusions: Similar to typical antidepressant drugs, SAM induces changes i n CaMKII activity and increases synapsin I level in HI and FCX nerve termin als, suggesting a modulatory action on transmitter release. Biol Psychiatry 2001;50:337-344 (C) 2001 Society of Biological Psychiatry.