Disease relevance of Nrgn

• The 80 kDa protein kinase C substrate from cell lysates and the 80-kDa phosphoprotein from intact cells appear to be identical, as indicated by peptide mapping with protease V8 from Staphylococcus aureus [1].
• 2) Are the low whole brain total T4 levels found in this mouse model associated with hypothyroidism, e.g. increased 5'-deiodinase type 2 (D2) activity and RC3-neurogranin messenger RNA levels [2]?
• Dissociation of phosphorylation and translocation of a myristoylated protein kinase C substrate (MARCKS protein) in C6 glioma and N1E-115 neuroblastoma cells [3].

High impact information on Nrgn

• The basal phosphorylation of protein kinase C substrate of relative molecular mass (Mr) 80,000 (80K) is significantly increased in all the ras-transformed cell lines [4].
• We constructed a vector for expression of a chimeric cDNA and hybrid protein consisting of the EGF-R extracellular, transmembrane and protein kinase C-substrate domains linked to the intracellular tyrosine kinase and carboxyl terminal domain of the rat neu cDNA [5].
• Here, we show that genetic overexpression of the growth-associated protein GAP-43, the axonal protein kinase C substrate, dramatically enhanced learning and long-term potentiation in transgenic mice [6].
• Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice [7].
• These results indicate a central role of Ng in the regulation of CaMKII activity with decisive influences on synaptic plasticity and spatial learning [7].

Biological context of Nrgn

• Here we show that deletion of the Ng gene in mice did not result in obvious developmental or neuroanatomical abnormalities but caused an impairment of spatial learning and changes in hippocampal short- and long-term plasticity (paired-pulse depression, synaptic fatigue, long-term potentiation induction) [7].
• Phorbol 12-myristate 13-acetate caused phosphorylation of Ng in WT mice and promoted the translocation of PKC from the cytosolic to the particulate fractions of both the WT and KO mice, albeit to a lesser extent in the latter [8].
• Attenuation of protein kinase C and cAMP-dependent protein kinase signal transduction in the neurogranin knockout mouse [8].
• RC3 is a neuronal calmodulin-binding protein and protein kinase C substrate that is thought to play an important regulatory role in synaptic transmission and neuronal plasticity [9].
• In addition, NG expression in the primate cerebellum by brush cells, which are excitatory, showed remarkable cell type-specific and species-specific expression patterns of a postsynaptic protein mediating calcium signaling mechanisms [10].

Anatomical context of Nrgn

• Neurogranin is expressed by principal cells but not interneurons in the rodent and monkey neocortex and hippocampus [11].
• In contrast, double-labeling experiments in rodents revealed that neocortical and hippocampal interneurons expressing glutamate decarboxylase 67 (GAD67) were consistently devoid of NG [11].
• By using immunocytochemistry and nonradioactive in situ hybridization, we demonstrate strong NG expression by principal cells in different neocortical layers and in the hippocampus by granule cells of the dentate gyrus and pyramidal neurons of CA1-CA3 [11].
• Expression of the protein kinase C substrate MARCKS and other heat-stable myristoylated proteins have been studied in four cultured neural cell lines [12].
• Purkinje cells in the central and nodular zones lose neurogranin expression between approximately P4 and P6, whereas expression in the posterior zone persists until approximately P20 [13].

Associations of Nrgn with chemical compounds

• Thyroid hormone-regulated genes potentially responsible for the learning deficit found in TRalpha(o/o) mice include GR, RC3 and GAP-43 [14].
• Age-related effects of ethanol consumption on triiodothyronine and retinoic acid nuclear receptors, neurogranin and neuromodulin expression levels in mouse brain [15].
• The inability to increase RC3 phosphorylation in mice lacking the gamma-subtype of protein kinase C by membrane depolarization or glutamate receptor activation may contribute to the spatial learning deficits and impaired hippocampal LTP observed in these mice [16].
• In the present study, using mouse hippocampal slices, we demonstrated that NMDA induced a rapid and transient phosphorylation and oxidation of Ng [17].
• However, physiological evidence for a role of RC3 in neuronal Ca(2+) dynamics is limited [9].

Regulatory relationships of Nrgn

• These results suggest that by its Ca2+-sensitive CaM-binding feature, and through its phosphorylation and oxidation, Ng regulates the Ca2+- and Ca2+/CaM-dependent signaling pathways subsequent to the stimulation of NMDA receptor [17].

Other interactions of Nrgn

• Results showed that 12% ethanol consumption in adult mice (11 months) induced an increase in RARbeta, RXRbetagamma and TRalphabeta mRNA level in the brain with only an increase in RC3 expression [15].
• Neurogranin expression identifies a novel array of Purkinje cell parasagittal stripes during mouse cerebellar development [13].
• RC3+/+ and RC3-/- cultures were indistinguishable with respect to neuron density, neuronal morphology, the formation of extensive neuritic networks and the presence of glial fibrillary acidic protein (GFAP)-positive astrocytes and gamma-aminobutyric acid (GABA)ergic neurons [9].
• Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein [18].
• SSeCKS, a major protein kinase C substrate with tumor suppressor activity, regulates G(1)-->S progression by controlling the expression and cellular compartmentalization of cyclin D [19].

Analytical, diagnostic and therapeutic context of Nrgn

• GAP-43 and RC3 protein levels also were measured by Western blot [15].
• From autoradiography, the endogenous substrate 17-kDa neurogranin, which was shown below 21 kDa, was mostly eluted by 100 mM KCl from the DE-52 column, whereas 43-kDa neuromodulin, which was also demonstrated in sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, only appeared in the 200 mM KCl eluates [20].
• Our previous digoxigenin in situ hybridization (DIG-ISH) studies detected RC3 mRNA in apical dendrites and cell bodies of neurons in the rat cerebral cortex and hippocampus [21].
• A commonly described Mr 80-kDa protein kinase C substrate (p80, 80 K, MARKS) was identified using 2D-PAGE, following phosphorylation in intact cells, and found to have reduced availability for phosphorylation in the transformed cell lines C4SE9, C1SA5 and NULB5 in comparison to the untransformed C4E10 and C1C10 [22].
• By using immunofluorescence for metabotropic glutamate receptor 2 (mGluR2) and neurogranin as markers, we demonstrate the existence of five non-overlapping subsets of Golgi cells: about 65% are glycinergic/GABAergic and co-express both markers [23].

References