PubMed: 27796283

Title
The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.
Journal
Nature communications
Volume
7
Issue
None
Pages
13282
Date
2016-10-31
Authors
Ip NY | Lai KO | Liang Z | Plattner F | Shen Y | Wong CC | Yates JR 3rd | Zhan Y

Evidence 1ed28a4963

These findings suggest that CaMKv is required for both synaptic transmission and protein synthesis-dependent LTP in the hippocampus.

Evidence 91176ce88f

Rac1 and RhoA are the best-studied members that regulate spine dynamics; their activation facilitates and prevents dendritic spine formation, respectively

Evidence bcf11dce44

In contrast, much less is known about how RhoA is regulated by excitatory glutamate receptors. The Rho-GEF Lfc (also known as GEF-H1) is one notable link between RhoA activity and glutamate receptors18. Lfc is inhibited by AMPA receptors; Lfc and RhoA inhibition is implicated in spine maintenance10. RhoA hyperactivity can lead to spine loss and impaired synaptic function.

Evidence 1d634d03f2

CaMKs functionally link NMDA (N-methyl-d-aspartate) receptors to Rac1 activation via the phosphorylation of specific guanine nucleotide exchange factors (GEFs) such as Kalirin-7, TIAM1 and β-PIX

Evidence 150d3a42a1

These observations suggest that CaMKv blocks RhoA activity by preventing its interaction with Lfc. These results demonstrate that CaMKv regulates spine maintenance through RhoA inhibition. The suppression of the Lfc/RhoA pathway by AMPA receptors is implicated in dendritic spine maintenance10. Given that CaMKv expression is upregulated by synaptic activity, CaMKv may be a key signalling protein that transduces the signals from AMPA receptors to suppress RhoA during activity-dependent spine maintenance. Corroborating this, the AMPA receptor blocker NBQX attenuated CaMKv expression in neurons (Fig. 3i,j). Importantly, CaMKv overexpression completely rescued NBQX-induced spine loss (Fig. 3k,l). These findings collectively reveal that activity-dependent CaMKv expression and the subsequent inhibition of Lfc/RhoA are required to mediate AMPA receptor function in spine maintenance.

Evidence ef9f2ca5e2

However, co-expression of the phospho-mimetic T345E failed to restore the defects in spine density after CaMKv depletion (Fig. 4l,m), suggesting that CaMKv phosphorylation by Cdk5 at Thr345 inhibits its function.

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