Differential CaMKII regulation by voltage-gated calcium channels in the striatum

Abstract

Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major calcium-dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ∼2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5 min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates.

Activated CaMKIIαBinds to the mGlu5Metabotropic Glutamate Receptor and Modulates Calcium Mobilization

“…Taken together, our data suggest an intriguing model in which the binding of CaM might confer a relatively transient Ca 21 -dependent modulation of mGlu 5a surface expression and signaling, but that increased CaMKIIa autophosphorylation at Thr286 would result in sustained binding to the CTD and longer-term modulation of mGlu 5a surface expression and Ca 21 mobilization. Since Thr286 autophosphorylation of CaMKII is sensitive to changes in the source, duration, or frequency of Ca 21 signals originating from multiple channels (Pasek et al, 2015), such as those occurring during synaptic plasticity, as well as to the regulated activities of protein phosphatases, this may provide a mechanism for cross talk with other signaling pathways.…”

The Ras-like GTPase Rem2 is a potent endogenous inhibitor of calcium/calmodulin-dependent kinase II activity

“…However, neither the precise mechanism of inhibition is known, nor is the relevance of this inhibition understood in more physiological context. CaMKII is an important modulator of high-voltage calcium channels and is directly involved in the frequency facilitation of the channel: phosphorylation of channels by CaMKII affects the channel conductance and inactivation properties (48)(49)(50)(51)(52)(53)(54)(55). We speculate that by being a powerful inhibitor of both, Rem2 might facilitate the interaction between CaMKII and high-voltage calcium channels, perhaps by acting as a scaffold to bridge between CaMKII and VGCCs, thereby providing a layer of channel regulation that is activity-dependent.…”

Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

“…In addition, the results show that PSAM 4 Finally, PSAM 4 -GlyR-induced depolarization may allow robust calcium influx via voltage-gated calcium channels and NMDA receptors relieved from voltage-dependent magnesium pore-block (31,32). Calcium influx activates calcium/calmodulin-dependent protein kinases (CaMKs), calcium response elements in genes, and various other signaling cascades (33,34), which are known to influence synaptic plasticity and behavior (35,36). Therefore, it is possible that when used to silence neurons, PSAM 4 -GlyR activation could potentially confound the interpretation of experimental results due to depolarization-induced calcium influx, independent of PSAM 4 -GlyR's effect on action potential firing like in the case of depolarization-block.…”