Prior to its identification in bovine and rat brain in 1991, 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.
Structure
Human neurogranin is a small protein consisting of 78 amino acids. 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.
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.
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.
Recent studies suggest that neurogranin also contributes to cardiovascular physiology. In cardiomyocytes it regulates calcium-dependent cardiac hypertrophy, and in endothelial cells it influences mitochondrial function and redox balance.
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, while another demonstrated reduced neurogranin immunoreactivity in the prefrontal cortex of affected individuals.
Neurogranin concentration in cerebrospinal fluid (CSF) has been investigated as a marker of synaptic dysfunction in age-related neurodegeneration. CSF neurogranin has been shown to be increased in patients with Alzheimer's disease. 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.
12Martínez 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. PMID9143500.
↑Ruano D, Aulchenko YS, Macedo A, Soares MJ, Valente J, Azevedo MH, etal. (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. hdl:1822/61620. PMID17140601.
↑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. PMID16797925. S2CID38984915.
