Brain expression of the calcineurin inhibitor RCAN1 (ADAPT78)
Center for Immunology and Microbial Disease, The Albany Medical College, Albany, NY 12208, USA. Archives of Biochemistry and Biophysics
(Impact Factor: 3.02).
12/2007; 467(2):185-92. DOI: 10.1016/j.abb.2007.08.030
RCAN1 (Adapt78) is an endogenous inhibitor of calcineurin, an important intracellular phosphatase that mediates many cellular responses to calcium. RCAN1 is expressed in multiple organs, especially heart, skeletal muscle and brain. In brain, it is thought to be important due to its strong expression, developmental regulation, abundance of target protein (calcineurin), and putative links to multiple brain-related disorders. Surprisingly, however, few studies have examined RCAN1 protein expression here. This has led to some confusion in the field over the exact nature and cell-type expression of isoform 4, the more studied of the two major RCAN1 protein isoforms, in brain. Here we characterize RCAN1 brain isoforms in more detail by assessing their size and distribution under conditions of calcium elevation, a hallmark of the isoform 4 response, and using rodent models to allow for more expanded analyses. We find that the 25-29kDa version of this protein, reported in many non-brain studies, is indeed also present in neurons, and most observable after calcium induction. We also observe that expression of isoform 4 is not specific to neurons, as both microglia and astrocyte cells in culture exhibit a strong induction of isoform 4 protein following calcium stress that is not observable in non-stressed tissue sections. Isoform 1 expression is also observable in a primary glial cell-type (rat microglia). Finally, our observations confirm previous reports of low or non-detectable constitutive isoform expression in non-stressed glia, and of a larger sized, RCAN1 antibody-interacting species. These studies extend and complement previous studies on RCAN isoforms toward better understanding the role of RCAN1 in brain function and as a potential new target for treating calcineurin-related brain disorders.
Available from: PubMed Central
- "The only calcineurin inhibitor which expression is regulated by calcium-calcineurin signaling is RCAN1, indicating that this protein can function in a feedback inhibition loop to suppress sustained calcineurin activity. RCAN1 is widely expressed in brain, both during development and in the adult and it has been postulated as a good candidate to contribute to mental disability in DS , , . Mouse models of RCAN1 overexpression have shown a role of RCAN1 regulating exocytosis in chromaffin cells and in mutant huntingtin phosphorilation, suggesting a role of RCAN1 in the Alzheimer's disease neuropathology associated to DS and in Huntington's disease , , . "
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ABSTRACT: DSCR1/ RCAN1 is a chromosome 21 gene found to be overexpressed in the brains of Down syndrome (DS) and postulated as a good candidate to contribute to mental disability. However, even though Rcan1 knockout mice have pronounced spatial learning and memory deficits, the possible deleterious effects of its overexpression in DS are not well understood. We have generated a transgenic mouse model overexpressing DSCR1/RCAN1 in the brain and analyzed the effect of RCAN1 overexpression on cognitive function. TgRCAN1 mice present a marked disruption of the learning process in a visuo-spatial learning task. However, no significant differences were observed in the performance of the memory phase of the test (removal session) nor in a step-down passive avoidance task, thus suggesting that once learning has been established, the animals are able to consolidate the information in the longer term.
Available from: onlinelibrary.wiley.com
- "Numerous inducers of RCAN1-4 expression have now been described including, most notably, calcium-elevating agents (Crawford et al., 1997; Kingsbury & Cunningham, 2000; Lin et al., 2003) and cell receptor agonists as summarized (Van Riper et al., 2008). Interestingly, the cell receptor agonists that have been reported are quite varied including anti-CD3 and anti-CD28 to stimulate T-cell activation; vascular endothelial growth factor (VEGF) to stimulate endothelial cell VEGF receptors; and angiotensin to stimulate angiotensin on rat smooth muscle cells (Mitchell et al., 2007). Our studies reveal a new class of cell receptor able to stimulate RCAN1-4 induction: toll-like receptors (TLRs). "
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ABSTRACT: Studies on the role of regulator of calcineurin 1 (RCAN1) in immunity are limited, but have demonstrated an involvement in T-lymphocyte function. Here, we expand these studies to macrophages and in vivo infection. The treatment of RAW and primary mouse macrophages with lipopolysaccharide from Escherichia coli strongly induced RCAN1 isoform 4 (RCAN1-4), but not isoform 1. RCAN1-4 induction involved calcium, calcineurin, and reactive oxygen species. Subsequent analysis with whole bacteria including gram-negative E. coli and gram-positive Staphylococcus aureus revealed strong RCAN1-4 inductions by both, and where tested, dependence on calcium. Staphylococcus aureus cell wall components peptidoglycan and lipoteichoic acid also strongly induced RCAN1-4. In vivo, a significant induction in the proinflammatory cytokines monocyte chemotactic protein-1, interleukin-6, interferon-γ, and tumor necrosis factor-α was observed in knockout (KO) lung vs. wild-type (WT) mice 7 days after nasal infection with Fransicella tularensis. This induction was not accompanied by a significant increase in F. tularensis burden in the KO lung. Additionally, a modest increase in respiratory burst activity in KO vs. WT macrophages was observed. Combined, these studies indicate that RCAN1 is involved in macrophage and the overall in vivo immune response, and provide additional evidence that RCAN1 plays an important role in cell immunity and infectious disease.
Available from: Damien J Keating
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