A CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus

doi:10.1016/S0028-3908(98)00229-9

Neuropharmacology

Volume 38, Issue 4, 1 April 1999, Pages 605-608

https://doi.org/10.1016/S0028-3908(98)00229-9 Get rights and content

Abstract

We have shown previously that activation of mGlu receptors using a group I specific mGlu receptor agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus (Palmer et al., 1997). We now report that DHPG-induced LTD is facilitated by treatment with KN-62, an inhibitor of certain Ca²⁺/calmodulin-dependent protein kinases (CaMKs), including CaMKII.

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Acknowledgements

Supported by the MRC and Knoll Pharmaceuticals. We are most grateful to Bill Anderson for providing the computer programmes.

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The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear. Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation (pT286), which induces Ca²⁺-independent autonomous kinase activity. In addition, we compared the role of pT286 among three forms of long-term plasticity (NMDAR-dependent LTP and LTD, and mGluR-dependent LTD) using simultaneous live imaging of endogenous CaMKII together with synaptic marker proteins. We determined that after LTP stimuli, pT286 autophosphorylation accelerated CaMKII movement to excitatory synapses. After NMDAR-LTD stimuli, pT286 was strictly required for any movement to inhibitory synapses. Similar to NMDAR-LTD, we found the mGluR-LTD stimuli did not induce CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, we demonstrate that the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Thus, despite its prominent role in LTP, we conclude that CaMKII T286 autophosphorylation is also required for both major forms of hippocampal LTD, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.
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The Ca²⁺/calmodulin (CaM)-dependent protein kinase II (CaMKII) was touted as a memory molecule, even before its involvement in long-term potentiation (LTP) was shown. The enzyme has not disappointed, with subsequent demonstrations of remarkable structural and regulatory properties. Its neuronal functions now extend to long-term depression (LTD), and last year saw the first direct evidence for memory storage by CaMKII. Although CaMKII may have taken the spotlight, it is a member of a large family of diverse and interesting CaM kinases. Our aim is to place CaMKII in context of the other CaM kinases and then review certain aspects of this kinase that are of current interest.
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Citation Excerpt :
Accordingly, interruption of CaMKII phosphorylation of Arc results in a gain-of-function phenotype, indicating that CaMKII normally acts to limit Arc-dependent synaptic weakening. A previous study reported that CaMKII inhibitor increases the magnitude of mGluR-LTD in the hippocampus (Schnabel et al., 1999), and CaMKII is activated during the process of scaling in response to increased activity (Shin et al., 2012). Just as CaMKII activity bound to NMDAR “records” the activity history of potentiated synapses (Lisman and Raghavachari, 2015), it is possible that CaMKII activity at non-potentiated synapses records the history of activity relevant for future mGluR-LTD.
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Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects
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Consistent with these studies, pharmacologic activation of D1-R or the AC markedly stimulates ERK activity and its phosphorylation in various neuronal cells.33,38–41 In addition, activation of group 1 metabotropic Glu receptors (mGluR1/5) has been shown to increase the intracellular Ca2+ and activate ERK signaling.42–45 Although the activation of DA D2 receptor (D2-R) inhibits PKA activity, D2-R stimulation also increases ERK signaling through PKC activation.46
Addiction to psychostimulants has been considered as a chronic psychiatric disorder characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that result in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction.
Autonomous CaMKII mediates both LTP and LTD using a mechanism for differential substrate site selection
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Citation Excerpt :
Although LTP requires protein kinase activity and particularly CaMKII, LTD requires protein phosphatase activity (Collingridge et al., 2010; Malenka and Bear, 2004; Xia and Storm, 2005) and a potential role of CaMKII is still unclear (Coultrap and Bayer, 2012). For mGluR-dependent LTD, previous findings were conflicting and indicated either inhibition (Mockett et al., 2011) or facilitation (Schnabel et al., 1999) by CaMKII inhibitors. For NMDAR-dependent LTD, an involvement of CaMKII has been attributed to presynaptic mechanisms (Stanton and Gage, 1996; Stevens et al., 1994) and the effect on synaptic strength mediated by postsynaptic AMPARs remains unexplored.
Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca²⁺/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced “autonomous” (Ca²⁺-independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by “autonomous” CaMKII was further stimulated by Ca²⁺/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference.
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2012, Neuropharmacology
Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluR). Although functional interplay between ionotropic N-methyl-d-aspartate receptors (NMDAR) and mGluR has been convincingly demonstrated in native and recombinant systems, the mechanism by which NMDAR activation leads to modulation of mGluR function has yet to be elucidated. Using whole-cell patch-clamp recordings in mouse nucleus accumbens (NAc) slices, we found that tetanic stimulation (TS) of excitatory afferents with a naturally occurring frequency (10 min at 13 Hz) reliably induces a mGluR1/5-dependent long-term depression (mGluR1/5-LTD) of excitatory synaptic transmission. Blockade of NMDAR during but not after TS showed enhanced mGluR1/5-LTD induction, which is associated with its antagonism of TS-induced calcium/calmodulin-dependent protein kinase II (CaMKII) activation. The ability of NMDAR antagonists to promote mGluR1/5-LTD induction was mimicked by a selective CaMKII inhibitor KN-62. However, the induction of mGluR1/5-LTD by bath-applied agonist (S)-3,5-dihydrophenylglycine was not affected by NMDAR blockade. We also observed that NMDAR or CaMKII blockade during TS significantly blunted TS-induced increased serine/threonine phosphorylation of the scaffold protein Homer1b/c and resulted in an increased interaction of mGluR5 with the Homer1b/c. These results indicate that synaptically released glutamate during TS of excitatory afferents can activate both NMDAR and mGluR1/5 in NAc neurons concomitantly and that activation of NMDAR may stimulate CaMKII-mediated phosphorylation of Homer1b/c and impair the interaction between mGluR5 and Homer1b/c, thereby attenuating mGluR1/5-LTD induction. This study provides a novel molecular mechanism by which NMDAR could regulate mGluR5 function.

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Rapid communicationA CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus

Abstract

Section snippets

Acknowledgements

Eur. J. Pharmacol.

Neuropharmacology

Neuropharmacology

Neurosci. Lett.

Neuron

Neuropharmacology

Rapid communication
A CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus