Critical role of regulator of calcineurin 1 in spinal cord injury

Wang, Guodong; Zhao, Yi‐Lei; Liu, Shenpeng; Jia, Jinling; Lu, Tan

doi:10.1007/s13105-016-0499-z

Cited by 8 publications

(7 citation statements)

References 38 publications

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“…RCAN1 is also overexpressed in the brains of individuals with Down syndrome, a disorder with an increased prevalence of AD . Neuronal expression of RCAN1 also increases with aging, and in response to traumatic stressors such as spinal cord injury and exhaustive exercise in muscle . The nutrient stress hyperglycaemia also induces RCAN1 expression in myotubes and pancreatic β‐cells .…”

Section: Rcan1 Expressionmentioning

confidence: 99%

The neuronal and endocrine roles of RCAN1 in health and disease

Peiris

Keating

2017

Clin Exp Pharma Physio

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The regulator of calcineurin 1 (RCAN1) was first discovered as a gene located on human chromosome 21, expressed in neurons and overexpressed in the brains of Down syndrome individuals. Increased expression of RCAN1 has been linked with not only Down syndrome-associated pathology but also an associated neurological disorder, Alzheimer's Disease, in which neuronal RCAN1 expression is also increased. RCAN1 has additionally been demonstrated to affect other cell types including endocrine cells, with links to the pathogenesis of β-cell dysfunction in type 2 diabetes. The primary functions of RCAN1 relate to the inhibition of the phosphatase calcineurin, and to the regulation of mitochondrial function. Various forms of cellular stress such as reactive oxygen species and hyperglycaemia cause transient increases in RCAN1 expression. The short term (hours to days) induction of RCAN1 expression is generally thought to have a protective effect by regulating the expression of pro-survival genes in multiple cell types, many of which are mediated via the calcineurin/NFAT transcriptional pathway. However, strong evidence also supports the notion that chronic (weeks-years) overexpression of RCAN1 has a detrimental effect on cells and that this may drive pathophysiological changes in neurons and endocrine cells linked to Down syndrome, Alzheimer's Disease and type 2 diabetes. Here we review the evidence related to these roles of RCAN1 in neurons and endocrine cells and their relationship to these human health disorders.

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Section: Rcan1 Expressionmentioning

confidence: 99%

The neuronal and endocrine roles of RCAN1 in health and disease

Peiris

Keating

2017

Clin Exp Pharma Physio

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“…Our previous work revealed that such a negative effect can be a major contributing factor to the hyperexcitability of small-diameter DRG neurons that is a basis of neuropathic pain induced by SCI (Ritter et al, 2015a). A recent study reported RCAN1 upregulation in the spinal cord dorsal horn after SCI (Wang et al, 2016). However, it was not clear whether the reported upregulation occurred in spinal neurons or synaptic terminals from primary sensory inputs in the dorsal horn.…”

Section: Novel Role Of Ntid Phosphorylation Sites On the Modulation Omentioning

confidence: 93%

“…Although these studies link reduced CaN activity and persistent pain syndromes, the downstream ion channel targets responsible for the underlying hyperexcitability are not known. A recent study reported upregulation of the endogenous regulator of CaN 1 (RCAN1) in rat spinal cord after SCI (Wang et al, 2016). RCAN1 upregulation typically inhibits CaN, which might affect CaN-dependent modulation of ion channels in DRG neurons (Davies et al, 2007;Liu et al, 2009;Li et al, 2011;Patel et al, 2015).…”

Section: Significance Statementmentioning

confidence: 99%

“…Alzheimer's disease, stroke, and Down syndrome (Cho et al, 2008;Patel et al, 2015;Kipanyula et al, 2016;Lee et al, 2016). After SCI, RCAN1 is also upregulated in the rat spinal cord (Wang et al, 2016). To test the role of RCAN1 in the SCI-induced dysregulated Kv3.4 function in the DRG, we first investigated the effect of unilateral cervical SCI on RCAN1 expression at the mRNA and protein levels in DRG sections ipsilateral to the injury using FISH and RCAN1 immunostaining, respectively (for antibody validation, see Materials and Methods).…”

Section: Sci Induces Upregulation Of the Rcan1 In Drg Neuronsmentioning

confidence: 99%

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Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K⁺ Channel Dysfunction in DRG Neurons

et al. 2017

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Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI. Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).

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“…This prevented CST retraction and improved motor function. Local lentivirus‐mediated RNA interference (RNAi) of the regulator of calcineurin 1 suppressed the increase in IL‐1β and TNF‐α and improved behavioral performance in injured rats . Local transfection of siRNA against the TNF‐like weak inducer of apoptosis decreased IL‐1β and TNF‐α, and enhanced locomotor functional recovery in injured mice …”

Section: Local Delivery Of Therapeutic Agents Regulates Inflammatory mentioning

confidence: 99%

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

et al. 2018

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The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI.

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Critical role of regulator of calcineurin 1 in spinal cord injury

Cited by 8 publications

References 38 publications

The neuronal and endocrine roles of RCAN1 in health and disease

The neuronal and endocrine roles of RCAN1 in health and disease

Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K⁺ Channel Dysfunction in DRG Neurons

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

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Critical role of regulator of calcineurin 1 in spinal cord injury

Cited by 8 publications

References 38 publications

The neuronal and endocrine roles of RCAN1 in health and disease

The neuronal and endocrine roles of RCAN1 in health and disease

Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

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Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K⁺ Channel Dysfunction in DRG Neurons