Role of Ca2+/Calmodulin-Dependent Protein Kinase Type II in Mediating Function and Dysfunction at Glutamatergic Synapses

Abstract

Glutamatergic synapses harbor abundant amounts of the multifunctional Ca2+/calmodulin-dependent protein kinase type II (CaMKII). Both in the postsynaptic density as well as in the cytosolic compartment of postsynaptic terminals, CaMKII plays major roles. In addition to its Ca2+-stimulated kinase activity, it can also bind to a variety of membrane proteins at the synapse and thus exert spatially restricted activity. The abundance of CaMKII in glutamatergic synapse is akin to scaffolding proteins although its prominent function still appears to be that of a kinase. The multimeric structure of CaMKII also confers several functional capabilities on the enzyme. The versatility of the enzyme has prompted hypotheses proposing several roles for the enzyme such as Ca2+ signal transduction, memory molecule function and scaffolding. The article will review the multiple roles played by CaMKII in glutamatergic synapses and how they are affected in disease conditions.

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“…Intracellular calcium is indispensable for this process [41,42]. Triggered by various stimuli, intracellular calcium overload occurs, which leads to the release of cytochrome C and apoptosis-inducing factors [43]. There is evidence that this is associated with neurodegenerative diseases [44,45].…”

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“…Recent investigations have indicated that the stimulation of extrasynaptic NMDA receptors containing GluN2B subunits leads to a persistent dephosphorylation of CREB, which is referred to as CREB shut-off [50]. As a result, CREB becomes transcriptionally inactive due to its fast dephosphorylation at serine 133 [51] the result indicates that an increase in Ca 2+ permeable AMPA receptors can initiate NMDA downstream signalling, potentially leading to the activation of the CREB-shut-off pathway in Parkinson's disease. Consequently, this impedes the activation of genes associated with plasticity, such as BDNF, resulting in impaired synaptic function, synapse loss, and eventual cellular death.…”

Dopamine, Psychosis, and Symptom Fluctuation: A Narrative Review

“…Importantly, NMDARs, AM-PARs, GABARs, and D2Rs all converge on CaMKII for downstream signal transduction and regulation (re-viewed in [ 10 ]). The beta (regulatory) subunit of CaMKII was found to be upregulated in schizophrenia, both in humans and in an animal model, indicating that it plays an essential role in the disease, likely by increasing the enzyme’s sensitivity to calcium signals [ 88 , 89 , 93 , 156 ]. CaMKII also controls several key phenotypic aspects of schizophrenia, such as enhanced amphetamine-induced dopamine release [ 42 , 94 , 95 , 98 ] and elevated D2High binding states [ 156 ].…”

“…In acute stress, CaMKII mediates the response to noradrenaline [ 87 ]. In individuals with increased levels of CaMKIIβ [ 88 , 89 ], this likely results in abnormal reactivity to stress [ 90 ] and dysregulation of the glutamatergic [ 91 ] and dopaminergic [ 82 ] systems (reviewed in [ 10 ]).…”

“…Furthermore, a key phenotypic marker of animal schizophrenia models, an increase in D2R levels in their high-affinity states (D2high), is also normalized by inhibition of CaMKII [ 1 , 97 ]. The CaMKIIβ subunit was found to be elevated in both humans with schizophrenia and in an animal model, suggesting it plays an important role in schizophrenia pathology in both species [ 10 , 88 , 93 , 97 , 98 ]. Therefore, CaMKII is a point of convergence of several key signaling pathways associated with schizophrenia symptoms and is able to mediate the effects of stress on this signaling network ( Figure 1 ).…”