Modification of presynaptic CaM kinase II affinity for ATP in hippocampus after long term blockade of serotonin reuptake.
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is markedly enriched at synapses, where it is involved in the control of synaptic transmission, transmitter release and synaptic plasticity. CaMKII has also been found to be involved in the long-term action of antidepressants on post-receptor signaling mechanisms, because monoamine reuptake inhibitors induced an increase in autophosphorylation and activity of the kinase in nerve terminals of hippocampus. To study whether changes in the amount of enzyme or kinetic changes, due to posttranslational modifications, are responsible for kinase activation in nerve terminals, alpha-CaMKII level and kinetic constants of the autophosphorylation reaction as a function of ATP concentration were measured in presynaptic cytosol from hippocampus. Treatment with two serotonin reuptake inhibitors did not change the level of presynaptic kinase or the Vmax of autophosphorylation reaction. Instead the Km of the kinase for ATP was decreased 2.8-fold with fluvoxamine and 3.5-fold with paroxetine, implying an increase in the affinity for ATP. This result represents the first finding of changes in kinetic constants of a major brain enzyme after treatment with antidepressant drugs.
Consogno
E
E
Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Milano, Italy.
Dorigo
C
C
Racagni
G
G
Popoli
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016666:Fluvoxamine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D008297:Male; D017374:Paroxetine / Q000494:pharmacology; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000255:Adenosine Triphosphate; D018687:Antidepressive Agents, Second-Generation; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016666:Fluvoxamine; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors