NMDA receptor activation stimulates transcription-independent rapid wnt5a protein synthesis via the MAPK signaling pathway

Wnts are secreted glycoproteins that regulate cell morphologies and behaviors by stimulating complicate intracellular signaling cascades. Previous work has established that Wnt signaling controls many oncogenic and developmental processes [1,2]. More recent studies have revealed that Wnt signaling is critically involved in key processes of the formation and plasticity of the nervous system, including neurogenesis [3], axon guidance [4], dendritic development [5], synaptic differentiation [6] and plasticity [7,8]. Abnormalities of Wnt signaling are implicated in major brain disorders such as Alzheimer's disease [9-11], Parkinson's disease [12,13], schizophrenia [14,15], and drug abuse [16]. Wnt5a is member of the Wnt protein family and plays important roles in outgrowth, guidance and branching of axons [17,18]; genesis of dopaminergic neurons [19]; and formation and plasticity of both excitatory and inhibitory synapses [20-22]. Wnt5a administration was reported to improve specific pathological processes of Alzheimer's [11] and Parkinson's diseases in animal models [12].Wnt proteins bind to receptors to activate the Wnt/β-catenin canonical pathway and β-catenin-independent non-canonical pathways, which include the planar cell polarity (PCP) pathway and the Wnt/calcium (Ca2+) pathway [2,23-26]. In the canonical pathway, Wnts (such as Wnt3a) inhibit glycogen synthase kinase 3β (GSK-3β) and consequently stabilize β-catenin to regulate transcription [1]. Wnt5a is a prototypic Wnt ligand that activates the non-canonical pathways [27,28]. The activation of the PCP pathway stimulates Rho GTPases and c-Jun N-terminal kinase (JNK) to regulate cell morphogenesis and movement [29], whereas the activation of the Wnt/Ca2+ pathway causes Ca2+ to activate protein kinase C (PKC) and calcium/calmodulin dependent protein kinase II (CaMKII) [30]. In neurons, Wnt secretion is intimately governed by synaptic activity, especially the activation of NMDA receptors (NMDAR) [7].In contrast to