Regulator of Calcineurin RCAN1 (DSCR1)
Regulator of calcineurin (RCAN) is a gene located in the region known as the Down syndrome critical region of human chromosome 21. It encodes a protein that can bind to and inhibit calcineurin, a serine/threonine protein phosphatase critical for learning, memory and synaptic plasticity. RCAN1 is expressed in several tissues and particularly high levels are found in brain and striated muscles. Expression levels respond to external stressors like Ca2+ and -amyloid. RCAN1 is involved in a number of cellular processes, including oxidative stress, angiogenesis, mitochondrial function and immune responses, some of which are calcineurin-independent. Importantly, RCAN is upregulated/overexpressed in certain pathological conditions including Alzheimer’s disease, cardiac hypertrophy, diabetes, degenerative neuropathy and Down syndrome, which makes it a strong candidate as a therapeutic target.
RCAN1 in Down syndrome
In 1995, J. Fuentes and colleagues identified RCAN1 as a new gene thought to be closely associated with the typical features of Down syndrome (DS) patients. They found structural characteristics in the gene that suggested it was involved in transcriptional regulation and/or signal transduction. Furthermore, it was found highly expressed in human brain and heart and upregulated in the brain of young rats as compared to old. It was thus suggested that overexpression of RCAN1 due to the presence of three copies of the gene as a result of trisomy 21, may be involved in the pathogenesis of DS, particularly in brain and heart related defects. Given the diverse functions of RCAN1 in different physiological contexts, its involvement in the pathogenesis of DS is predicted to be complex.
RCAN1 is overexpressed across tissues in DS, including brain, heart and skeletal muscle. In the brain, RCAN1 overexpression is involved in a decline in neurogenesis, long-term potentiation and learning and memory, while it increases neurodegeneration and contributes to aggregate formation and Alzheimer-like pathology in DS.
In the immune system, RCAN1 overexpression has been implicated in the decline in the innate immune response and T-cell function, which could contribute to at least some of the immune problems found in people with DS, that are more susceptible to infections and show a high incidence of haematopoietic malignancies and certain autoimmune disorders such as autoimmune thyroid disease, coeliac disease and diabetes.
On the other hand, some protective effects of RCAN1 overexpression are also observed in people with DS, like decrease inflammation and allergic responses and a very low incidence of solid tumours and angiogenesis.
- Galambos C. (2019): RCAN1- driven pulmonary endothelial cell dysfunction leads to pulmonary hypoplasia and pulmonary hypertension in Down syndrome.
- Ryeom S. (2020): Calcineurin signalling in Neutrophils may underlie the high incidence of infection-related mortality for children with Down syndrome being treated for leukaemia.
- Marti E. (2007): Molecular mechanisms underlying RCAN1/DSCR1-mediated neuronal death and its relevance to Down syndrome and neurodegenerative diseases.
- Barallobre MJ. (2007): Role of Dyrk1a and DSCR1 during the development of cortical dendrite. Implications in Down syndrome.
- Crawford D. (2009): The role and targeting of RCAN1 in Down syndrome.
- Pritchard M. (2009): The role of Down syndrome-related gene DSCR1/RCAN1 in learning and memory.
- Hoeffer C. (2018): RCAN1, synaptic plasticity and neuronal phosphatase dysregulation in Down syndrome.
More information about RCAN1….
The RCAN Gene
The RCAN1 gene was initially referred as DSCR1 because its location within the Down syndrome critical region (DSCR) in chromosome 21, which is hypothesized to contain the genes responsible for the major DS phenotypes. Features within the DSCR1 gene sequence, predicted it could be involved in transcriptional regulation and/or signal transduction. Soon after, it was shown that DSCR1 forms a complex with and regulates the activity of the Ca2+/calmodulin-dependent serine/threonine phosphatase calcineurin, whose substrates include nuclear factor of activated T-cells (NFAT), a transcription factor that regulates gene expression in many cell types, thereby regulating different physiological events via dephosphorylation of important substrates. Because of its broad expression and complexity of responses across tissues and circumstances, a suite of different names were utilized for the same gene/protein product. Moreover, different nomenclature was used across different species. Thus, the name RCAN1 was proposed in an effort to avoid confusion and facilitate research across different models and fields. RCAN1 is conserved across species, from lower unicellular eukaryotes such as yeast to higher organisms including humans. This high level of conservation between species, indicates a conserved role during evolution.
The RCAN gene consists of seven exons separated by six introns. Four transcripts are produced by alternatively splicing and all messenger RNA (mRNA) isoforms share exons five through seven. Isoforms RCAN1-1 and RCAN1-4 are the most abundant and most studies of the RCAN1 isoforms. RCAN1-1 comprise exons 1, 5, 6 and 7, and encodes a protein of 252 amino acids most highly expressed in heart, brain, skeletal muscle and pancreas. Isoform RCAN1-4 comprises exons 4, 5, 6 and 7, encoding a 197 amino acid protein that is most highly expressed in heart, liver, muscle, placenta, pancreas and kidney. The isoform containing exon 2 has been reported only in fetal liver and brain, and isoform 3 has not yet been detected. All isoforms share the 168 amino acids at the C-terminal region that contain the calcineurin binding site. N-terminal regions vary and may confer different and/or specific functions to the different isoforms. A number of studies in different model systems, have shown that RCAN1 is primarily present in cytoplasm, although can localise to mitochondria and nucleus.
Different promoters control the expression of RCAN1-1 and RCAN1-4 isoforms, suggesting that they have different regulatory mechanisms and possibly even different functions. For example, while the RCAN1-1 promoter responds to glucocorticoids, the RCAN1-4 does not. But, expression of RCAN1-4 is strongly induced by elevated intracellular Ca2+ levels, while there is no evidence that RCAN1-1 responds in the same way. Moreover, the promoters are differentially activated in different tissues, for instance, RCAN1-1 basal levels are higher that RCAN1-4 in most tissues, including brain. Phosphorylation of RCAN1 on different sites regulates its activity towards calcineurin, its subcellular localization and protein stability. Additionally, acetylation by HDAC3 increases RCAN1 protein stability and promotes its nuclear translocation.
Tissue expression and potential involvement in pathologies:
RCAN1 is expressed in many tissues, but the highest expression levels have been found in brain, heart and striated muscles. RCAN1 overexpression due to the extra copy of the gene in trisomy 21, contributes to mental retardation and congenital cardiac defects. RCAN1 levels are also increased in other clinical conditions, including Alzheimer disease, cardiac hypertrophy, diabetes and degenerative neuropathy. Furthermore, expression levels respond to external stressors such as reactive oxygen species, elevated intracellular Ca2+, protein aggregates, and hormonal changes.
RCAN1 has been implicated in a variety of cellular processes, including oxidative stress, angiogenesis, mitochondrial function and immune responses. Most of these functions have been attributed to its interaction with the calcineurin pathway because RCAN1 inhibits calcineurin activity, modulating calcineurin-dependent transcriptional responses/signalling pathways, thereby regulating a number of physiological events via dephosphorylation of important substrates. Nonetheless, calcineurin-independent activities have been demonstrated. Briefly, RCAN1 has been found to be involved in:
- Mitochondria homeostasis by helping to maintain mitochondrial functional and structural stability and by regulating mitophagy.
- Pro-apoptotic activity through activation of caspase-3 and caspase-9
- RNA binding and stabilization of messenger RNA in the nucleus.
- Epigenetic regulation of adult neurogenesis through modulation of the epigenetic factors TET1 and miR-124.
- Cardiovascular sustainability through circadian oscillations of the RCAN1/calcineurin pathway.
- Obesity and thermorigenesis.
- Insulin responses and hyperglycemia.
- Nephropathy and kidney diseases.
- Axon outgrowth.
- Activity-dependent muscle development.
- Learning and memory through calcineurin signalling.
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