DEFINITION
Neurogranin (NRGN) is the human homolog of the neuron-specific rat RC3/neurogranin gene. This gene encodes a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium.
It is suggested that the NRGN is a direct target for thyroid hormone in human brain, and that control of expression of this gene could underlay many of the consequences of hypothyroidism on mental states during development as well as in adult subjects.
THE GENE
The NRGN gene contains four exons and three introns. The exons 1 and 2 encode the protein and exons 3 and 4 contain untranslated sequences.
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
mRNA synthesis
Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin). 1994
Iñiguez MA, Morte B, Rodriguez-Peña A, Muñoz A, Gerendasy D, Sutcliffe JG, Bernal J.
- RC3 encodes a thyroid hormone-dependent, calmodulin-binding, protein kinase C substrate (neurogranin, p17) present in the dendritic spines of discrete neuronal populations in the forebrain. Its physiological role could be related to synaptic plasticity, memory, and other processes. In the present work we have isolated and sequenced 2.4 kbp of genomic DNA upstream from the origin of transcription and determined its nucleotide sequence. The major features of the RC3 promoter are the absence of TATA and CAAT boxes and the presence of an Initiator sequence surrounding the cap site. By sequence analysis we identified several cis-acting regulatory elements, among them response elements for retinoic acid and steroid (glucocorticoids/progesterone) hormone receptors. An oligonucleotide containing the retinoic acid responsive element bound to retinoic acid receptors specifically in vitro and conferred retinoic acid regulation to a heterologous promoter after transfection in COS-7 cells. Retinoic acid and dexamethasone, respectively, increased activity of the RC3 promoter in neuroblastoma cells when a deletion construct containing the retinoic acid and the glucocorticoid responsive elements was cotransfected with retinoic acid receptor or glucocorticoid receptor expression vectors. When added together all-trans retinoic acid and dexamethasone had additive effects. 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. Our results suggest that the expression of RC3 in vivo could be subject to complex physiological signals, including retinoids and steroid hormones in addition to thyroid hormones.
Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin). 1994
Our results suggest that the expression of RC3 in vivo could be subject to complex physiological signals, including retinoids and steroid hormones in addition to thyroid hormones.
Cocaine decreases expression of neurogranin via alterations in thyroid receptor/retinoid X receptor signaling,2013
In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other hypothalamic-pituitary-thyroid signaling factors.
neurogranin expression thyroid
protein synthesis
post-translational modifications
Ca2+–calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains, 1999
degradation
CELLULAR FUNCTIONS
cellular localization, (dendrites)
Dendritic translocation of RC3/neurogranin mRNA in normal aging, Alzheimer disease and fronto-temporal dementia. 1997
- RC3/neurogranin is a postsynaptic protein kinase C (PKC)-/calmodulin-binding substrate implicated in long-term potentiation (LTP) forms of synaptic plasticity. 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. This observation suggested that RC3 mRNA is selectively translocated to dendrites, where it may be translated locally in response to synaptic activity. To test this hypothesis further, we isolated a full-length cDNA clone of the homologous human RC3 mRNA from a human cortex lambda GT11 library, determined its nucleotide and predicted amino acid sequences, and performed mRNA expression studies in cerebral cortex from normal human patients and from patients with Alzheimer disease (AD) and fronto-temporal dementia (FTD). The human cDNA clone detects a single approximately 1.3 kb mRNA whose nucleotide sequence is 73% similar to the rat nucleotide sequence and 96% similar to its amino acid sequence. DIG-ISH studies detect robust staining of RC3 mRNA in cell bodies of numerous neurons throughout Layers II-VI and in both apical and basal dendrites of pyramidal neurons in human neocortex (temporal/frontal). We conclude that dendritic targeting of RC3 mRNA is conserved in human brain. In AD neocortex tissue, there is little or no evidence for RC3 mRNA translocation to dendrites, while in FTD neocortex, targeting of RC3 mRNA to apical dendrites is preserved. Comparative studies in AD and FTD point to the potential importance of synapse integrity and the dendritic cytoskeleton in RC3 mRNA targeting in the human neocortex.
RNA localization in neurite morphogenesis and synaptic regulation: current evidence and novel approaches. 2010
Only the latter localizes to dendrites, and both this short and a truncated version (BDNFklox) are restricted to the cell body, corresponding to reduced dendritic protein levels.
biological function
Ca(2+) sensor proteins in dendritic spines: a race for Ca(2+). 2012
The affinity of RC3 and CaM binding reduces significantly at higher [Ca2+] and gets completely abolished upon phosphorylation of RC3 by protein kinase C (Gerendasy et al. ).
Signaling logic of activity-triggered dendritic protein synthesis: an mTOR gate but not a feedback switch.2009
In the absence of such 5′TOP targeting, other dendritic mRNAs are translated, including Arc, αCaMKII, microtubule-associated protein 2 (MAP2), neurogranin and interestingly BDNF itself
Molecular switches at the synapse emerge from receptor and kinase traffic.2005
Some current proposals for such bistable synaptic switches include the calcium calmodulin type II kinase (CaMKII) hypothesis, a mitogen-activated protein kinase (MAPK) feedback loop, and, recently, the mammalian target of rapamycin*(mTOR)* protein synthesis loop..
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
Neurogranin mTOR
Neurogranin BDNF
Neurogranin methylation
Neurogranin myristoylation
DIAGNOSTIC USE
Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis. 2007
