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  • Key molecules in the EP second messenger

    2020-06-16

    Key molecules in the EP1 second messenger signaling cascade that are necessary for potentiation of GluK2/GluK5 were identified. We also identified three GluK5 serines located BAY-6076 in a membrane-proximal C-terminal domain that, when mutated to the phosphomimetic aspartate and expressed with GluK2, rendered the receptor insensitive to EP1 modulation, as if this construct had been “pre-potentiated”. The peak potentiation of heteromeric kainate receptors following activation of mGlu1 was reached within 3min and then gradually declined (Rojas et al., 2013). This gradual decline of mGlu1 potentiated kainate receptor currents was attributed to the activation of phosphatases as it was absent in cells pre-treated with the phosphatase inhibitor okadaic acid (Rojas et al., 2013). Contrary to potentiation by mGlu1, heteromeric kainate receptor currents potentiated by EP1 continually increased with time (Fig. 6C), and pretreatment with okadaic acid did not significantly affect the average peak kainate receptor currents following EP1 activation (Fig. 8C). Therefore, unlike the modulation of heteromeric kainate receptors by group I metabotropic glutamate receptors (Rojas et al., 2013), termination of potentiation by EP1 is likely mediated by different phosphatases, which suggests that EP1 activation engages mechanisms in addition to PKC that modulate kainate receptors. The modulation of NMDA receptors following engagement of a Gαq signaling cascade proceeds through a more elaborate signaling cascade. Activation of mGlu5 or the M1 BAY-6076 receptor results in the activation of PKC that subsequently phosphorylates the Src complex protein PYK2, in turn activating Src tyrosine kinase, which phosphorylates a tyrosine residue in the C-terminus of NMDA receptor subunit GluN2B that alters the surface expression of this subunit (MacDonald et al., 2007). Unlike NMDA receptors, the potentiation of heteromeric kainate receptors by EP1 activation appears to be Src independent as it was not affected by pretreatment with lavendustin A (a Src tyrosine kinase inhibitor). This is a key difference in the regulation of kainate and NMDA receptors by Gαq coupled GPCR activation, as ionotropic glutamate receptors are interwoven in multiple membrane protein complexes that alter receptor function (Rojas and Dingledine, 2013). Heteromeric and homomeric kainate receptors appear to have distinct post-translational modification potential. For example, homomeric GluK2 receptors are phosphorylated by both PKC and PKA (Chamberlain et al., 2012, Konopacki et al., 2011, Kornreich et al., 2007, Nasu-Nishimura et al., 2010, Raymond et al., 1993, Raymond et al., 1994, Traynelis and Wahl, 1997, Wang et al., 1993), whereas heteromeric GluK2 containing kainate receptors are modulated by activation of PKC but not PKA (Figs. 8B, C and Rojas et al., 2013). In addition to regulation by PKA and PKC, homomeric GluK2 receptors can also be SUMOylated at a C-terminal consensus site resulting in receptor endocytosis and consequent altered synaptic excitability and transmission (Chamberlain et al., 2012, Konopacki et al., 2011, Martin et al., 2007, Wilkinson et al., 2008, Wilkinson et al., 2012), as well as palmitoylated at C-terminal cysteine residues (Pickering et al., 1995). These post-translational modifications of GluK2 are not mutually exclusive. In fact, phosphorylation of the C-terminus of GluK2 by PKC promotes both palmitoylation and SUMOylation, suggesting a functional network of PKC, SUMOylation and palmitoylation that regulates surface expression of GluK2 containing kainate receptors (Konopacki et al., 2011, Pickering et al., 1995). Although homomeric GluK2 receptors are SUMOylated and palmitoylated, little is known regarding these post-translational modifications of heteromeric GluK2 containing receptors (e.g. GluK2/Gluk5 and GluK2/GluK4). Further investigation is necessary to determine whether heteromeric GluK2 containing receptors are regulated by SUMOylation and palmitoylation and whether there is a subsequent change in receptor trafficking or function.