Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders.
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, Ca2+ /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.
Popoli
M
M
Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milano, Italy. maurizio.popoli@unimi.it
Mori
S
S
Brunello
N
N
Perez
J
J
Gennarelli
M
M
Racagni
G
G
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001923:Brain Chemistry / Q000187:drug effects; D002135:Calcium-Binding Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D019964:Mood Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D009473:Neuronal Plasticity; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050857:Synaptotagmins
D000928:Antidepressive Agents; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D050857:Synaptotagmins; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases