Second messenger-regulated protein kinases in the brain: Their functional role and the action of antidepressant drugs

Depression has been treated pharmacologically for over three decades, but t he views regarding the mechanism of action of antidepressant drugs have reg istered recently a major change. It was increasingly appreciated that adapt ive changes in postreceptor signaling pathways, rather than primary action of drugs on monoamine transporters, metabolic enzymes, and receptors, are c onnected to therapeutic effect. For some of the various signaling pathways affected by antidepressant treatment, it was shown that protein phosphoryla tion, which represents an obligate step for most pathways, is markedly affe cted by long-term treatment. Changes were reported to be induced in the fun ction of protein kinase C, cyclic AMP-dependent protein kinase, and calcium /calmodulin-dependent protein kinase, For two of these kinases (cyclic AMP- and calcium/calmodulin-dependent), the changes have been studied in isolat ed neuronal compartments (microtubules and presynaptic terminals). Antidepr essant treatment activates the two kinases and increases the endogenous pho sphorylation of selected substrates (microtubule-associated protein 2 and s ynaptotagmin). These modifications may be partly responsible for the change s induced by antidepressants in neurotransmission. The changes in protein p hosphorylation induced by long-term antidepressant treatment may contribute to explain the therapeutic action of antidepressants and suggest new strat egies of pharmacological intervention.