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Gene Review

Nrgn  -  neurogranin

Rattus norvegicus

Synonyms: Neurogranin, Ng, Protein kinase C substrate 7.5 kDa protein, RC3
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Disease relevance of Nrgn


Psychiatry related information on Nrgn

  • The control of RC3 mRNA is so far the only molecular event known to be regulated by thyroid hormone once the critical periods of brain development are over and could represent a molecular correlate for the age-independent, reversible alterations induced by hypothyroidism in the adult brain [6].
  • Sleep deprivation differentially alters the mRNA and protein levels of neurogranin in rat brain [7].

High impact information on Nrgn

  • A homologous sequence in the 3'UTR of neurogranin, transcripts of which also reside in dendrites, also funtioned in cis to promote its dendritic transport [8].
  • Adult rat brain is sensitive to thyroid hormone. Regulation of RC3/neurogranin mRNA [6].
  • Rats thyroidectomized on postnatal day 40 and killed three months later showed a decreased RC3 mRNA concentration in the cerebral cortex and striatum [6].
  • In the present work we show that adult-onset hypothyroidism leads to a reversible decrease of RC3 mRNA [6].
  • The RC3 IRES was most active and was further characterized after transfection in primary neurons [9].

Chemical compound and disease context of Nrgn

  • In contrast to other molecular targets of thyroid hormone in the brain, such as myelin genes, expression of RC3 was also affected by long term hypothyroidism in the absence of hormone replacement, indicating that thyroid hormone is a required factor for the cell-specific control of RC3 expression [10].

Biological context of Nrgn

  • We speculate that the redox state of Ng, similar to the state of phosphorylation of this protein, may regulate the level of CaM, which in turn modulates the activities of CaM-dependent enzymes in the neurons [11].
  • Neurogranin/RC3 is a neuron-specific, Ca(2+)-sensitive calmodulin binding protein and a specific protein kinase C substrate [12].
  • Somatic RC3 was found in cyto- and nucleoplasmic compartments of all neuronal phenotypes (medium spiny, medium aspiny, and large aspiny cells) [13].
  • Single amino acid mutagenesis indicated that residues within the IQ domain are important for CaM binding to neurogranin in vivo [14].
  • When comparing the rate of DEANO-mediated nitrosation of Ng with other sulfhydryl-containing compounds, it became evident that Ng ranked as one of the best NO acceptors among those tested, including serum albumin, glutathione, and dithiothreitol [15].

Anatomical context of Nrgn


Associations of Nrgn with chemical compounds


Physical interactions of Nrgn

  • These results indicate that modification of NG to form intramolecular disulfides outside the IQ domain provides an alternative mechanism for regulation of its binding affinity to CaM [16].

Enzymatic interactions of Nrgn

  • CaM also failed to protect DEANO-mediated oxidation of PKC-phosphorylated Ng with or without Ca2+ [15].

Regulatory relationships of Nrgn

  • This work indicates that the Ca(2+) binding properties of calmodulin are highly regulated and reveals a role for RC3 in accelerating the dissociation of Ca(2+)-calmodulin target complexes at the end of a Ca(2+) signal [17].

Other interactions of Nrgn

  • S100 was ineffective in inhibiting the phosphorylation of Nm and Ng without Ca2+ and only poorly effective in the presence of Ca2+ [18].
  • We identified among these proteins an 85, 80 kDa and the tau protein as specific substrates for protein kinase A (PKA), MARCKS, and neurogranin as specific substrates for protein kinase C (PKC), and prostaglandin-D-synthase as substrate for casein kinase II (CKII) [19].
  • Despite the fact that RC3 expression in vivo is thyroid hormone-dependent, no evidence for the presence of a thyroid hormone responsive element was found within the 2.4 kbp flanking region analyzed and thyroid hormone did not increase reporter activity after cotransfection of suitable constructs with thyroid hormone receptor expression vectors [2].
  • For microtubule-associated protein 2 (MAP-2), neurogranin, and the glutamate receptor subtype B-flip, no correlation was observed in any cell field between synaptic enhancement and hybridization to the mRNA [20].
  • Moreover, it is noteworthy that neurogranin, the full-length protein of W-NG(28-43) and a relevant PKC substrate in the forebrain, binds PtdIns(3,4,5)P3 with high affinity [21].

Analytical, diagnostic and therapeutic context of Nrgn

  • In the absence of Ca2+, RC3 formed a stoichiometric complex with CaM as evidenced by an increase in the M(r) determined by gel filtration chromatography [22].
  • Identification of the Cys residues of rat brain Ng, Cys3, Cys4, Cys9, and Cys51, involved in NO-mediated intramolecular disulfide bridge formation was examined by site-directed mutagenesis [23].
  • These treatments, as well as those by other oxidants, all resulted in an increase in thiolation of proteins; among them, thiolation of Ng was positively identified by immunoprecipitation [24].
  • To identify thyroid hormone-sensitive neuronal populations in the forebrain, we studied the effects of thyroid hormone deficiency and replacement on the expression of RC3 messenger RNA (mRNA) in the rat brain by in situ hybridization [10].
  • Northern blot analysis and in situ hybridization experiments show that RC3 mRNA is highly enriched in rat brain, with restricted expression in neuronal subsets primarily in the cortex, striatum, and hippocampus as well as certain nuclei within the thalamus, hypothalamus, the olfactory bulb [25].


  1. Thyroid hormone regulation of RC3, a brain-specific gene encoding a protein kinase-C substrate. Iñiguez, M.A., Rodriguez-Peña, A., Ibarrola, N., Aguilera, M., Muñoz, A., Bernal, J. Endocrinology (1993) [Pubmed]
  2. Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin). Iñiguez, M.A., Morte, B., Rodriguez-Peña, A., Muñoz, A., Gerendasy, D., Sutcliffe, J.G., Bernal, J. Brain Res. Mol. Brain Res. (1994) [Pubmed]
  3. RC3/neurogranin structure and expression in the caprine brain in relation to congenital hypothyroidism. Piosik, P.A., van Groenigen, M., Ponne, N.J., Bolhuis, P.A., Baas, F. Brain Res. Mol. Brain Res. (1995) [Pubmed]
  4. MAP2 and neurogranin as markers for dendritic lesions in CNS injury. An immunohistochemical study in the rat. Li, G.L., Farooque, M., Lewen, A., Lennmyr, F., Holtz, A., Olsson, Y. APMIS (2000) [Pubmed]
  5. Triiodothyronine administration reverses vitamin A deficiency-related hypo-expression of retinoic acid and triiodothyronine nuclear receptors and of neurogranin in rat brain. Husson, M., Enderlin, V., Alfos, S., Féart, C., Higueret, P., Pallet, V. Br. J. Nutr. (2003) [Pubmed]
  6. Adult rat brain is sensitive to thyroid hormone. Regulation of RC3/neurogranin mRNA. Iñiguez, M.A., Rodriguez-Peña, A., Ibarrola, N., Morreale de Escobar, G., Bernal, J. J. Clin. Invest. (1992) [Pubmed]
  7. Sleep deprivation differentially alters the mRNA and protein levels of neurogranin in rat brain. Neuner-Jehle, M., Rhyner, T.A., Borbély, A.A. Brain Res. (1995) [Pubmed]
  8. Two cis-acting elements in the 3' untranslated region of alpha-CaMKII regulate its dendritic targeting. Mori, Y., Imaizumi, K., Katayama, T., Yoneda, T., Tohyama, M. Nat. Neurosci. (2000) [Pubmed]
  9. Internal initiation of translation of five dendritically localized neuronal mRNAs. Pinkstaff, J.K., Chappell, S.A., Mauro, V.P., Edelman, G.M., Krushel, L.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  10. Cell-specific effects of thyroid hormone on RC3/neurogranin expression in rat brain. Iniguez, M.A., De Lecea, L., Guadano-Ferraz, A., Morte, B., Gerendasy, D., Sutcliffe, J.G., Bernal, J. Endocrinology (1996) [Pubmed]
  11. N-methyl-D-aspartate induces neurogranin/RC3 oxidation in rat brain slices. Li, J., Pak, J.H., Huang, F.L., Huang, K.P. J. Biol. Chem. (1999) [Pubmed]
  12. Structural and dynamic characterization of a neuron-specific protein kinase C substrate, neurogranin. Ran, X., Miao, H.H., Sheu, F.S., Yang, D. Biochemistry (2003) [Pubmed]
  13. Localization of the protein kinase C phosphorylation/calmodulin-binding substrate RC3 in dendritic spines of neostriatal neurons. Watson, J.B., Sutcliffe, J.G., Fisher, R.S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  14. Interactions between neurogranin and calmodulin in vivo. Prichard, L., Deloulme, J.C., Storm, D.R. J. Biol. Chem. (1999) [Pubmed]
  15. Nitric oxide modification of rat brain neurogranin affects its phosphorylation by protein kinase C and affinity for calmodulin. Sheu, F.S., Mahoney, C.W., Seki, K., Huang, K.P. J. Biol. Chem. (1996) [Pubmed]
  16. Calcium-sensitive interaction between calmodulin and modified forms of rat brain neurogranin/RC3. Huang, K.P., Huang, F.L., Li, J., Schuck, P., McPhie, P. Biochemistry (2000) [Pubmed]
  17. RC3/Neurogranin and Ca2+/calmodulin-dependent protein kinase II produce opposing effects on the affinity of calmodulin for calcium. Gaertner, T.R., Putkey, J.A., Waxham, M.N. J. Biol. Chem. (2004) [Pubmed]
  18. Differential responses of protein kinase C substrates (MARCKS, neuromodulin, and neurogranin) phosphorylation to calmodulin and S100. Sheu, F.S., Huang, F.L., Huang, K.P. Arch. Biochem. Biophys. (1995) [Pubmed]
  19. Age-dependent differences in glutamate-induced phosphorylation systems in rat hippocampal slices. Angenstein, F., Buchner, K., Staak, S. Hippocampus. (1999) [Pubmed]
  20. Protein kinase C and F1/GAP-43 gene expression in hippocampus inversely related to synaptic enhancement lasting 3 days. Meberg, P.J., Barnes, C.A., McNaughton, B.L., Routtenberg, A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  21. Selective recognition of phosphatidylinositol 3,4,5-trisphosphate by a synthetic peptide. Lu, P.J., Chen, C.S. J. Biol. Chem. (1997) [Pubmed]
  22. Characterization of a 7.5-kDa protein kinase C substrate (RC3 protein, neurogranin) from rat brain. Huang, K.P., Huang, F.L., Chen, H.C. Arch. Biochem. Biophys. (1993) [Pubmed]
  23. Nitric oxide modification of rat brain neurogranin. Identification of the cysteine residues involved in intramolecular disulfide bridge formation using site-directed mutagenesis. Mahoney, C.W., Pak, J.H., Huang, K.P. J. Biol. Chem. (1996) [Pubmed]
  24. Glutathiolation of proteins by glutathione disulfide S-oxide derived from S-nitrosoglutathione. Modifications of rat brain neurogranin/RC3 and neuromodulin/GAP-43. Li, J., Huang, F.L., Huang, K.P. J. Biol. Chem. (2001) [Pubmed]
  25. Subtractive cDNA cloning of RC3, a rodent cortex-enriched mRNA encoding a novel 78 residue protein. Watson, J.B., Battenberg, E.F., Wong, K.K., Bloom, F.E., Sutcliffe, J.G. J. Neurosci. Res. (1990) [Pubmed]
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