Neurogranin

NRGN
Identifiers
AliasesNRGN, RC3, hng, neurogranin
External IDsOMIM: 602350; MGI: 1927184; HomoloGene: 136802; GeneCards: NRGN; OMA:NRGN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4900

64011

Ensembl

ENSG00000154146

ENSMUSG00000053310

UniProt

Q92686

P60761

RefSeq (mRNA)

NM_006176
NM_001126181

NM_022029

RefSeq (protein)

NP_001119653
NP_006167

NP_071312

Location (UCSC)Chr 11: 124.74 – 124.75 MbChr 9: 37.46 – 37.46 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Neurogranin is a calmodulin-binding protein expressed primarily in the brain, particularly in dendritic spines, and participating in the protein kinase C signaling pathway. Neurogranin has also been identified in aortic endothelial cells and cardiomyocytes.[5][6] It is the main postsynaptic protein regulating the availability of calmodulin by binding to it in the absence of calcium.

History

Prior to its identification in bovine and rat brain in 1991,[7] neurogranin was known as a putative protein kinase C-phosphorylated protein named p17. Human neurogranin was cloned in 1997 and was found to be 96% identical to the rat protein.[8]

Structure

Human neurogranin is a small protein consisting of 78 amino acids.[8] Neurogranin belongs to a family of neuron-enriched calmodulin-binding proteins, together with neuromodulin (GAP-43), sharing a conserved central motif that functions both as the protein kinase C phosphorylation site and the calmodulin-binding domain.[7]

The protein contains an IQ motif (consensus sequence IQXXXRGXXXR), a characteristic sequence found in several calmodulin-binding proteins that mediates preferential binding to apo-calmodulin (calcium-free calmodulin). Phosphorylation of this region by protein kinase C reduces the affinity of neurogranin for calmodulin and modulates its signaling properties.[7]

Function

Neurogranin regulates intracellular calmodulin availability and functions as a key component of protein kinase C signaling. It preferentially binds calmodulin in the absence of calcium, whereas phosphorylation by protein kinase C reduces its calmodulin-binding capacity.

Expression of the NRGN gene is regulated by thyroid hormones through a thyroid hormone-responsive element located in the first intron.[9]

Recent studies suggest that neurogranin also contributes to cardiovascular physiology. In cardiomyocytes it regulates calcium-dependent cardiac hypertrophy,[10] and in endothelial cells it influences mitochondrial function and redox balance.[11]

Clinical significance

Genetic and neuropathological evidence has implicated neurogranin in schizophrenia. One study reported an association between variation in the NRGN gene and increased risk of schizophrenia in males,[12] while another demonstrated reduced neurogranin immunoreactivity in the prefrontal cortex of affected individuals.[13]

Neurogranin concentration in cerebrospinal fluid (CSF) has been investigated as a marker of synaptic dysfunction in age-related neurodegeneration.[14] CSF neurogranin has been shown to be increased in patients with Alzheimer's disease.[15][16] In particular, the ratio of CSF neurogranin truncated at P75 to the beta-secretase BACE1 has been proposed as a potential marker of cognitive deterioration during progression of Alzheimer's disease.[17]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000154146 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000053310 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Jorgensen AN, Abdullah CS, Bhuiyan MS, Watt M, Dominic P, Kolluru GK, et al. (August 2022). "Neurogranin regulates calcium-dependent cardiac hypertrophy". Experimental and Molecular Pathology. 127 104815. doi:10.1016/j.yexmp.2022.104815. PMC 11118017. PMID 35870494. S2CID 250941689.
  6. ^ Jorgensen AN, Rashdan NA, Rao KN, Delgadillo LF, Kolluru GK, Krzywanski DM, et al. (April 2024). "Neurogranin expression regulates mitochondrial function and redox balance in endothelial cells". Redox Biology. 70 103085. doi:10.1016/j.redox.2024.103085. PMC 10878108. PMID 38359746.
  7. ^ a b c Baudier J, Deloulme JC, Van Dorsselaer A, Black D, Matthes HW (January 1991). "Purification and characterization of a brain-specific protein kinase C substrate, neurogranin (p17). Identification of a consensus amino acid sequence between neurogranin and neuromodulin (GAP43) that corresponds to the protein kinase C phosphorylation site and the calmodulin-binding domain". The Journal of Biological Chemistry. 266 (1): 229–237. doi:10.1016/S0021-9258(18)52425-X. PMID 1824695.
  8. ^ a b Martínez de Arrieta C, Pérez Jurado L, Bernal J, Coloma A (April 1997). "Structure, organization, and chromosomal mapping of the human neurogranin gene (NRGN)". Genomics. 41 (2): 243–249. doi:10.1006/geno.1997.4622. PMID 9143500.
  9. ^ Martínez de Arrieta C, Morte B, Coloma A, Bernal J (January 1999). "The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron". Endocrinology. 140 (1): 335–343. doi:10.1210/en.140.1.335. hdl:10261/24257. PMID 9886843.
  10. ^ Jorgensen AN, Abdullah CS, Bhuiyan MS, Watt M, Dominic P, Kolluru GK, et al. (August 2022). "Neurogranin regulates calcium-dependent cardiac hypertrophy". Experimental and Molecular Pathology. 127 104815. doi:10.1016/j.yexmp.2022.104815. PMC 11118017. PMID 35870494. S2CID 250941689.
  11. ^ Jorgensen AN, Rashdan NA, Rao KN, Delgadillo LF, Kolluru GK, Krzywanski DM, et al. (April 2024). "Neurogranin expression regulates mitochondrial function and redox balance in endothelial cells". Redox Biology. 70 103085. doi:10.1016/j.redox.2024.103085. PMC 10878108. PMID 38359746.
  12. ^ Ruano D, Aulchenko YS, Macedo A, Soares MJ, Valente J, Azevedo MH, et al. (January 2008). "Association of the gene encoding neurogranin with schizophrenia in males". Journal of Psychiatric Research. 42 (2): 125–133. doi:10.1016/j.jpsychires.2006.10.008. PMID 17140601.
  13. ^ Broadbelt K, Ramprasaud A, Jones LB (October 2006). "Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex". Schizophrenia Research. 87 (1–3): 6–14. doi:10.1016/j.schres.2006.04.028. PMID 16797925. S2CID 38984915.
  14. ^ Casaletto KB, Elahi FM, Bettcher BM, Neuhaus J, Bendlin BB, Asthana S, et al. (October 2017). "Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers". Neurology. 89 (17): 1782–1788. doi:10.1212/WNL.0000000000004569. PMC 5664306. PMID 28939668.
  15. ^ De Vos A, Jacobs D, Struyfs H, Fransen E, Andersson K, Portelius E, et al. (December 2015). "C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer's disease". Alzheimer's & Dementia. 11 (12): 1461–1469. doi:10.1016/j.jalz.2015.05.012. PMID 26092348.
  16. ^ Willemse EA, De Vos A, Herries EM, Andreasson U, Engelborghs S, van der Flier WM, et al. (June 2018). "Neurogranin as Cerebrospinal Fluid Biomarker for Alzheimer Disease: An Assay Comparison Study". Clinical Chemistry. 64 (6): 927–937. doi:10.1373/clinchem.2017.283028. hdl:10067/1495100151162165141. PMID 29523639.
  17. ^ De Vos A, Struyfs H, Jacobs D, Fransen E, Klewansky T, De Roeck E, et al. (July 2016). "The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease". Journal of Alzheimer's Disease. 53 (4): 1523–1538. doi:10.3233/JAD-160227. PMC 4981899. PMID 27392859.
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