Calcium/calmodulin‐dependent kinase II is involved in the facilitating effect of clozapine on NMDA‐ and electrically evoked responses in the medial prefrontal cortical pyramidal cells

Abstract

Using the method of intracellular recording in in vitro brain slices, we investigated whether calcium/calmodulin-dependent kinase II (CaMKII) is involved in the facilitating action produced by the atypical antipsychotic drug (APD) clozapine on N-methyl-D-aspartate (NMDA)-induced inward currents and electrically evoked excitatory postsynaptic currents (EPSCs) in pyramidal cells of the medial prefrontal cortex (mPFC). The CaMKII inhibitor, KN-93 (N-[2-(N-(4-Chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-4-methoxybenzenesulfonamide), but not the inactive isomer, KN-92 (2-[N-(4-Methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, phosphate), blocked clozapine's augmenting effect on NMDA-evoked responses in pyramidal cells of the rat mPFC. KN-93 also inhibited the facilitatory effect of clozapine on electrically evoked responses in the pyramidal cells, while KN-92 did not show any effect. Similarly, the calmodulin antagonist W-7 (N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide) inhibited the augmenting effect of clozapine on NMDA- and electrically evoked responses in the pyramidal cells. To further test the role of CaMKII in mediating the augmenting action of clozapine, we performed experiments in alpha-CaMKII mutant and wild-type mice. In contrast to results in pyramidal cells from rats or wild-type mice, clozapine was not able to potentiate NMDA-induced currents in the mPFC pyramidal cells from the CaMKII mutant mouse. Both KN-93 and W-7, but not KN-92, inhibited the augmenting action of clozapine in the pyramidal cells of wild-type mice. Taken together, these results suggest that the facilitating action of clozapine on the NMDA- and electrically evoked responses in pyramidal cells of the mPFC requires activation of CaMKII enzyme.

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

“…In our studies, a possible mechanism by which these clinically effective antipsychotic agents attenuated the acute inhibitory effects of dizocilpine on miR-219 concentrations is by decreasing the neurochemical and behavioral deficits associated with NMDA receptor hypofunction. Consistent with this hypothesis, it has been shown that haloperidol and clozapine can facilitate NMDA receptor function (44) and counter the inhibitory effects of dizocilpine on NMDA receptor-mediated transmission (45).…”

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

“…In fact, chlorpromazine and other phenothiazine derivatives are recognized calmodulin antagonists and clozapine has been found to reduce ERK1/2-MAPK (Pozzi et al, 2003;Ratnakar et al, 1995). These kinases may play a role in the mechanism of action of those antipsychotics which inhibit their activity, for example, clozapine, chlorpromazine, but not in the mechanism underlying the action of other drugs which enhance ERK-MAPK or CaMK activity (Ninan et al, 2003;Pozzi et al, 2003;Yang et al, 2004). Moreover, the lack of chlorpromazine and clozapine effect on phospho-Ser-133-CREB level rather excluded their action via this pathway.…”

“…Specifically, an involvement of some enzymes, which are known to be changed in schizophrenia and are affected by antipsychotic drugs, that is, PKA, protein kinase C (PKC), protein kinase B (PKB; Akt), glycogen synthase kinase-3 (GSK-3), Ca 2 + /calmodulin-dependent protein kinase (CaMK), and mitogen-activated protein kinase (MAPK), in the inhibitory action of chlorpromazine and clozapine on CRH gene promoter activity was determined (Dwivedi and Pandey, 1999;Dwivedi et al, 2002;Lu et al, 2004;Ninan et al, 2003;Yang et al, 2004). We chose for this study chlorpromazine, a classical antipsychotic drug and a atypical antipsychotic clozapine, because in the first part of study they showed the most potent inhibitory effects on the CRH gene activity.…”

Neuregulin1 (NRG1) Signaling through Fyn Modulates NMDA Receptor Phosphorylation: Differential Synaptic Function inNRG1+/−Knock-Outs Compared with Wild-Type Mice

“…This increase is dependent on protein kinase A, calcium/calmodulin-dependent kinase II, and SFKs. In the nucleus accumbens, clozapine only affects NR2B subunit-containing NMDARs (Ninan et al, 2003;Wittmann et al, 2005). Subtle misregulation of membrane potential, ligand binding, or tyrosine phosphorylation may have profound effects on NMDAR opening, thus influencing behaviors modulated by this channel (Moghaddam, 2003).…”