Enhanced NMDA Receptor-Mediated Synaptic Transmission, Enhanced Long-Term Potentiation, and Impaired Learning and Memory in Mice Lacking IRSp53

Abstract

IRSp53 is an adaptor protein that acts downstream of Rac and Cdc42 small GTPases and is implicated in

Functional and Physical Interaction of Diacylglycerol Kinase ζ with Protein Kinase Cα Is Required for Cerebellar Long-Term Depression

“…Primary antibodies used were rabbit or guinea pig anti-DGK (K. Kim et al, 2009), mouse anti-PKC␣ (BD Biosciences), mouse (Sigma), rabbit (Sigma), or guinea pig (Synaptic Systems) anti-calbindin, mouse anti-metabotropic glutamate receptor 1 (mGluR1, BD Biosciences), mouse anti-FLAG (M2, Sigma), rabbit anti-synapsin 1/2 (Synaptic Systems), mouse anti-␤-actin (Santa Cruz Biotechnology), rabbit anti-mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/Erk, Cell Signaling Technology), rabbit antiphosphorylated MAPK (Cell Signaling Technology), rabbit anti-GluA2 (Millipore), rabbit anti-PICK1 (Abcam), and rabbit anti-PSD-93/ chapsyn-110 (1634) (M.H. Kim et al, 2009) antibodies.…”

“…In the case of long-term depression (LTD) at synapses between parallel fibers (PFs) and Purkinje cells in the cerebellum, a large number of signaling molecules have been implicated to be involved Hirano, 2013;Kim and Tanaka-Yamamoto, 2013). Many of these molecules can be categorized as positive regulators, and protein kinase C (PKC) has long been known to be necessary and even sufficient for LTD (Linden and Connor, 1991;Hartell, 1994;De Zeeuw et al, 1998;Endo and Launey, 2003;Kondo et al, 2005).…”

“…Many of these molecules can be categorized as positive regulators, and protein kinase C (PKC) has long been known to be necessary and even sufficient for LTD (Linden and Connor, 1991;Hartell, 1994;De Zeeuw et al, 1998;Endo and Launey, 2003;Kondo et al, 2005). Although the pathway and functions of PKC activation during LTD have been well understood (Hirano, 2013;Kim and Tanaka-Yamamoto, 2013), it is not clear as to how PKC activity is precisely regulated. Another question remains regarding isoform specificity.…”

“…Therefore, DGK can be considered a negative regulator of PKC, which can be activated by DAG. The DGK isoform DGK was shown to be targeted to excitatory synapses by its interaction with postsynaptic density protein-95 (PSD-95) family proteins and to regulate synaptic morphology and functions in hippocampal pyramidal neurons (K. Kim et al, 2009Kim et al, , 2010Seo et al, 2012). In a study using an in vitro assay and cultured cell lines, it was demonstrated that DGK reduces PKC␣ activity by interacting with PKC␣ and metabolizing DAG, whereas such regulation of PKC␣ by DGK is attenuated by PKC␣-dependent phosphorylation of DGK and by subsequent dissociation of PKC␣ from DGK (Luo et al, 2003a,b).…”

“…In a study using an in vitro assay and cultured cell lines, it was demonstrated that DGK reduces PKC␣ activity by interacting with PKC␣ and metabolizing DAG, whereas such regulation of PKC␣ by DGK is attenuated by PKC␣-dependent phosphorylation of DGK and by subsequent dissociation of PKC␣ from DGK (Luo et al, 2003a,b). Given that DGK is expressed at high levels in cerebellar Purkinje cells (Hozumi et al, 2003;K. Kim et al, 2009), the mutual regulation of DGK and PKC␣ may be crucial for the local and fine regulation of PKC␣ activity at synapses upon the stimulation triggering LTD.…”