A Wnt/Calcium Signaling Cascade Regulates Neuronal Excitability and Trafficking of NMDARs

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Andrea McQuate, Elena Latorre-Esteves, Andres Barria
Wnt signaling controls multiple biological process, particularly the embryonic development of metazoans. Sustained expression of Wnt signaling components in the mature mammalian CNS and their apparent deregulation in certain neuropathologies suggest that it also plays a part beyond embryonic development to regulate normal brain function. We describe a noncanonical Wnt/Ca²⁺ signaling cascade that regulates the electrophysiological intrinsic properties of rat neurons, resulting in sustained membrane depolarization and the mobilization of Ca²⁺ from internal stores. These effects require tyrosine kinase-like orphan receptor 2 (RoR2), activation of PLC, and voltage-gated Ca²⁺ channels. Activation of this signaling cascade then promotes surface expression of N-methyl-D-aspartate receptors (NMDARs) through a SNARE-dependent mechanism. This neuronal Wnt/Ca²⁺ signaling pathway represents a mechanism for Wnt ligands to regulate normal brain processes in the mature animal and provides a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders where NMDARs are compromised.

Graphical abstract

Teaser

Wnt signaling is a highly conserved signaling mechanism that controls multiple biological processes. McQuate et al. identify a noncanonical Wnt signaling cascade that regulates electrophysiological intrinsic properties of neurons, resulting in sustained membrane depolarization, mobilization of Ca²⁺ from internal stores, and increased surface expression of NMDAR-type glutamate receptors.


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