The Down Syndrome Critical Region Protein RCAN1 Regulates Long-Term Potentiation and Memory via Inhibition of Phosphatase Signaling

Hoeffer, Charles A.; Dey, Asim; Sachan, Nita; Wong, Helen; Patterson, Richard J.; Shelton, John M.; Richardson, James A.; Klann, Eric; Rothermel, Beverly A.

doi:10.1523/jneurosci.3974-07.2007

Cited by 102 publications

(96 citation statements)

References 59 publications

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“…Consistent with this notion, the RCAN1 knockout mice exhibited significant defects in spatial learning and memory, reduced associative cued memory, and impaired late-phase long-term potentiation (L-LTP), a form of synaptic plasticity dependent on PKA (37). This report suggests that RCAN1 provides a restriction on calcineurin activity during memory formation.…”

Section: Discussionmentioning

confidence: 57%

“…Decreased calcineurin activity by overexpression of RCAN1 has been proposed to result in increased hyperphosphorylation of tau, leading to the formation of neurofibrillary tangles (14,37). Because calcineurin activity regulates the rate of inactivation of critical effector such as CREB, it seems likely that overexpression of RCAN1, as observed in DS and AD, may enhance CREB signaling by blocking calcineurin activity.…”

Section: Discussionmentioning

confidence: 99%

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The Regulator of Calcineurin 1 (RCAN1/DSCR1) Activates the cAMP Response Element-binding Protein (CREB) Pathway

Kim

Seo

2011

Journal of Biological Chemistry

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Background:The regulator of the calcineurin 1 (RCAN1) gene is located on human chromosome 21, the trisomy of which causes Down syndrome (DS). Results: RCAN1 increases the phosphorylation of transcription factor CREB. Conclusion: RCAN1 activates CREB signaling by inhibition of calcineurin activity. Significance: Identification of RCAN1 as a CREB signaling regulator could contribute to the understanding of DS pathogenesis.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

The Regulator of Calcineurin 1 (RCAN1/DSCR1) Activates the cAMP Response Element-binding Protein (CREB) Pathway

Kim

Seo

2011

Journal of Biological Chemistry

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“…Ϫ/Ϫ mice show impairments in spatial learning and memory (21), and knockdown or overexpression of the Drosophila melanogaster RCAN1 homolog leads to severe learning defects (22). RCAN1 has therefore been proposed as a candidate protein responsible for mental retardation in DS.…”

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confidence: 99%

Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

Jung

Park

Ryu

et al. 2011

Journal of Biological Chemistry

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“…RCANs bind to and inhibit CN-mediated activities in vitro (13)(14)(15)(16)(17)(18). The evidence in these studies comes mostly from overexpression of RCANs, but the CN-inhibitory potential of these proteins is also shown in some mouse models of Rcan1 loss of function (19)(20)(21)(22). However, the phenotypes of null mutants of Saccharomyces cerevisiae Rcn1p (23) and Rcan1 Ϫ/Ϫ or Rcan2 Ϫ/Ϫ mice (19,24) are compatible with reduced CN activity, which has led to suggestions of a positive action of RCANs on CN.…”

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confidence: 99%

The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators

Martı́nez-Martı́nez

Genescà

Rodrı́guez

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Specificity of signaling kinases and phosphatases toward their targets is usually mediated by docking interactions with substrates and regulatory proteins. Here, we characterize the motifs involved in the physical and functional interaction of the phosphatase calcineurin with a group of modulators, the RCAN protein family. Mutation of key residues within the hydrophobic docking-cleft of the calcineurin catalytic domain impairs binding to all human RCAN proteins and to the calcineurin interacting proteins Cabin1 and AKAP79. A valine-rich region within the RCAN carboxyl region is essential for binding to the docking site in calcineurin. Although a peptide containing this sequence compromises NFAT signaling in living cells, it does not inhibit calcineurin catalytic activity directly. Instead, calcineurin catalytic activity is inhibited by a motif at the extreme C-terminal region of RCAN, which acts in cis with the docking motif. Our results therefore indicate that the inhibitory action of RCAN on calcineurin-NFAT signaling results not only from the inhibition of phosphatase activity but also from competition between NFAT and RCAN for binding to the same docking site in calcineurin. Thus, competition by substrates and modulators for a common docking site appears to be an essential mechanism in the regulation of Ca 2؉ -calcineurin signaling.docking interaction ͉ NFAT ͉ PxIxIT ͉ Cabin1 ͉ phosphatase P rotein kinases and phosphatases are central to many intracellular signal transduction processes. In general, these signaling proteins rely on binding interactions both for interaction with upstream regulators and for enzymatic modification of substrates. In some cases, these interactions are mediated by dedicated modular domains fused to the catalytic domain. In others, the binding surfaces are within the catalytic domain but do not overlap the active site. Both these binding interactions are known as docking interactions and are envisaged principally as a mechanism to increase substrate specificity (1). The serine/threonine protein phosphatase calcineurin (CN, PP2B) uses both of these binding strategies to organize its interactome. CN is a heterodimer composed of a catalytic subunit calcineurin A (CnA) and a regulatory subunit CnB. The phosphatase domain in CnA is connected, through a sequence known as the linker, to a regulatory region that acts as a protein-protein interacting platform and includes binding domains for CnB and calmodulin (CaM) and an autoinhibitory (AI) segment. Increases in intracellular Ca 2ϩ allow interaction of CaM with heterodimeric CN, displacing AI from the active site to allow CN to dephosphorylate its substrates (2). The bestcharacterized CN-substrate interaction is that with members of the nuclear factor of activated T cells (NFAT) family of transcription factors (3). The N-terminal region of NFAT proteins contains 2 CN-binding sites, neither of which contains the substrate motif. These docking motifs are the PxIxIT sequence (4) and the LxVP motif (5, 6). Two CnA regions are important for int...

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The Down Syndrome Critical Region Protein RCAN1 Regulates Long-Term Potentiation and Memory via Inhibition of Phosphatase Signaling

Cited by 102 publications

References 59 publications

The Regulator of Calcineurin 1 (RCAN1/DSCR1) Activates the cAMP Response Element-binding Protein (CREB) Pathway

The Regulator of Calcineurin 1 (RCAN1/DSCR1) Activates the cAMP Response Element-binding Protein (CREB) Pathway

Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators

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