Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders Maurizio Popoli a, *, Silvia Mori a , Nicoletta Brunello b , Jorge Perez c , Massimo Gennarelli d , Giorgio Racagni a,d a Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy b Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Via Campi 183, 41100 Modena, Italy c Istituto Scientifico HSR, Department of NeuropsychiatryÐUniversity Vita e Salute, Via Stamira d'Ancona 20, 20127 Milano, Italy d IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy Abstract It is currently a widely accepted opinion that adaptive, plastic changes in the molecular and cellular components of neuronal signaling systems correlate with the effects on mood and cognition observed after long-term treatment with antidepressant drugs. Protein phosphorylation represents a key step for most signaling systems, and it is involved in the regulation of virtually all cellular functions. Two serine/threonine kinases, Ca 2+ /calmodulin-dependent protein kinase II and cyclic AMP-dependent protein kinase, have been shown to be activated in the brain following antidepressant treatment. The changes in kinase activity are mirrored by changes in the phosphorylation of selected protein substrates in subcellular compartments (presynaptic terminals and microtubules), which, in turn, may contribute to the modulation of synaptic transmission observed with antidepressants. The molecular consequences of protein kinase activation may account for some of the alterations in neural function induced by antidepressants, and may suggest novel possible strategies of pharmacological intervention. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Protein kinase; Antidepressant; CaM kinase; cAMP-dependent kinase; Synaptotagmin; Synaptic plasticity Abbreviations: AC, adenylate cyclase; ACTH, adrenocorticotropic hormone; BDNF, brain-derived neurotrophic factor; C subunit, catalytic subunit; CaMKII, Ca 2+ /calmodulin-dependent protein kinase II; cAMP, cyclic AMP; CREB, cyclic AMP response element-binding protein; CRF, corticotropin-releasing factor; DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32 kDa; DMI, desmethylimipramine; ECS, electroconvulsive shock; G i , inhibitory G-proteins to adenylate cyclase; G s , stimulatory G-proteins to adenylate cyclase; HPA, hypothalamic ±pituitary ±adrenal; 5-HT, 5- hydroxytryptamine, serotonin; KAP, kinase anchoring protein; LTP, long-term potentiation; MAO, monoamine oxidase; MAP, microtubule-associated protein; NA, noradrenaline; NT, neurotrophin; PKA, protein kinase A; PKC, Ca 2+ /phospholipid-dependent protein kinase; PSD, postsynaptic density; R subunit, regulatory subunit; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SNARE, N-ethylmaleimide-sensitive fusion factor attachment protein receptor; SSRI, selective serotonin reuptake inhibitor; syt, synaptotagmin; TH, tyrosine hydroxylase; TrkB, tyrosine kinase receptor B. Contents 1. Introduction ............................................ 150 1.1. Protein kinases and protein phosphorylation: implications for antidepressant drug action. 151 2. Antidepressant treatment and Ca 2+ /calmodulin-dependent protein phosphorylation ........ 151 2.1. Ca 2+ /calmodulin-dependent protein kinase II in the brain ................. 151 2.2. Modifications induced by antidepressant treatment in Ca 2+ /calmodulin-dependent protein phosphorylation .................................. 152 * Corresponding author. Tel.: +39-02-20488331; fax: +39-02-29403673. E-mail address: maurizio.popoli@unimi.it (M. Popoli). Pharmacology & Therapeutics 89 (2001) 149 ± 170 0163-7258/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII:S0163-7258(00)00108-X