Previous Neural Activity Regulates AMPA-Receptor Trafficking via Wnt Signal Pathway
Introduction
The wnt signaling family is a secreted glycoprotein family in which members bind to the Frizzled receptors to activate the scaffold protein Dishevelled (Wayman, G. A., S. Impey, et al. 2006). Wnt is named after a combination of two genes: the Wg (wingless) and the Int ( Rijsewijk, 1987). The wingless gene had originally been identified in Drosophila melanogaster functioning in embryogenesis (C. Nusslein-Volhard, 1980). The Int genes were originally identified as vertebrate genes near several integration sites of mouse mammary tumor virus (MMTV) (R. Nusse, 1986)
Wnt signaling family proteins mediate numerous developmental events, including activity-dependent dendrite development (Wayman, Impey et al. 2006). Indeed dendritic abnormalities are the most consistent pathologic correlate of mental retardation including Down’s syndrome and Fragile X syndrome (Wayman, Impey et al. 2006).
Wnt-Frizzled signaling can occur through at least three different pathways: the canonical or Wnt/b-catenin pathway, the planar cell polarity pathway (PCP), and the Wnt/calcium pathway (Alvania, Chen et al. 2006). CaMKIV (Calcium/calmodulin-dependent protein kinase IV) is predominantly nucleus (Jensen et al., 1991), where it regulates gene transcription through phosphorylation of cAMP response element-binding protein (CREB) and CREB binding protein (CBP) (Enslen et al., 1994; Impey et al., 2002).
NMDAR-dependent calpain activation and b-catenin-mediated gene regulation, merging together in neurons, form a novel mechanism for activity-dependent gene expression (Abe and Takeichi 2007). Wayman et al. identify an NMDA (N-methyl D-aspartate) receptor-mediated, Ca2+-dependent signaling pathway that couples neuronal activity to dendritic arborization through enhanced synthesis and secretion of Wnt-2 (Figure 1)(Wayman, Impey et al. 2006). Further the expression of Wnt-2 stimulates dendritic arborization and growth. Although the signaling pathways that regulate Wnt synthesis and secretion are being defined, little is known about whether secreted wnt modifies the potential of synaptic plasticity.
AMPA receptor (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). AMPARs are found in many parts of the brain and are the most commonly found receptor in CNS. AMPARs are composed of four types of subunits which are GluR1, GluR2, GluR3, and GluR4. AMPARs are heterotetrameric, consisting of symmetric 'dimer of dimers' of GluR2 and either GluR1, GluR3 or GluR4 (Song I 2002).
The GluR1 subunit plays a key role in hippocampal LTP maintenance and is regulated by protein phosphorylation at several major sites on its intracellular carboxyl-terminal domain. The threshold for GluR1 synaptic incorporation during LTP can be lowered by phosphorylation at these sites. (Hu, Real et al., 2007). The functional role of phosphorylation of Ser831 and Ser845 sites, in particular, has been extensively studied. Ser831 is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC), whereas Ser845 is phosphorylated by PKA (Figure 1). Phosphorylation of these sites regulates both the channel functions and the receptors’ synaptic trafficking and incorporation (Hu, Real et al. 2007).
Slusarski, Corces et al’s results indicate that some Wnt proteins work through specific Frizzled homologues to stimulate the phosphatidylinositol signalling pathway via heterotrimeric G-protein subunits (Slusarski, Corces et al. 1997). CaMKII and PKC are down-stream kinases of phosphatidylinositol signaling pathway. The phosphorylation of Ser831 by CaMKII and PKC can regulate the synaptic incorporation of the AMPAR (Hu, Real et al. 2007).
In summary, all of the above can be connected to draw series of events in the following (Figure 1): activity-dependent Wnt gene expression is dependent upon intracellular calcium signaling. High calcium activated CaMKII and then CaMKIγ. CaMKIγ translocate to the nucleus and triggers wnt gene transcription via phosphorylating CREB. Wnt protein is secreted and wnt-Frizzled signaling occurs via wnt/calcium pathway and activates CaMKII and PKC. CaMKII and PKC phosphorylate GluR2/3 on Ser831 site and promote AMPA-receptor trafficking to synapse.

Fig1 Previous neural activity stimulate NMDAR and wnt protein is produced to enhance dendritic arborization and AMPAR trafficking.
Reference
Abe, K. and M. Takeichi (2007). "NMDA-receptor activation induces calpain-mediated beta-catenin cleavages for triggering gene expression." Neuron 53(3): 387-97.

Alvania, R. S., X. Chen, et al. (2006). "Calcium signals control Wnt-dependent dendrite growth." Neuron 50(6): 813-5.

C. Nusslein-Volhard and E. Wieschaus (1980) "Mutations affecting segment number and polarity in Drosophila" in Nature Volume 287, pages 795-801.

F. Rijsewijk, M. Schuermann, E. Wagenaar, P. Parren, D. Weigel and R. Nusse (1987) "The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless" in Cell Volume 50, pages 649-657.

Hu, H., E. Real, et al. (2007). "Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking." Cell 131(1): 160-73.

R. Nusse, A. van Ooyen, D. Cox, Y. K. Fung and H. Varmus (1984) "Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15" in Nature Volume 307, pages 131-136.

Song I, Huganir RL (2002). "Regulation of AMPA receptors during synaptic plasticity". Trends Neurosci. 25 (11): 578–88. doi:10.1016/S0166-2236(02)02270-1

Slusarski, D. C., V. G. Corces, et al. (1997). "Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling." Nature 390(6658): 410-3.

Wayman, G. A., S. Impey, et al. (2006). "Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2." Neuron 50(6): 897-909.