Neuronal Calcium Sensor 1 Has Two Variants with Distinct Calcium Binding Characteristics

Wang, Baisheng; Boeckel, Göran Ramin; Huynh, Larry; Nguyen, Lien D.; Cao, Wenxiang; Cruz, Enrique M. De La; Kaftan, Edward; Ehrlich, Barbara E.

doi:10.1371/journal.pone.0161414

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…Cell proliferation was then assessed using a luminescencebased assay that measures the number of viable cells based on the level of ATP present, but no significant difference in proliferation was seen between WT and NCS1 KO cells (Fig. 5D), consistent with previous findings (Moore et al, 2017;Wang et al, 2016). These results demonstrate an important role for NCS1 in cell survival and migration, but not cell proliferation.…”

Section: Ncs1 Ko Renders Cells Deficient In Colony Formation and Migr...supporting

confidence: 87%

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

et al. 2020

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Changes in intracellular calcium (Ca 2+ ) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca 2+ -binding protein that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified. In this study, we aimed to determine (a) whether NCS1 expression changes in response to external stimuli, (b) the importance of NCS1 for cell survival and migration, and (c) the cellular mechanism(s) through which NSC1 modulates these outcomes. We found that NCS1 abundance increases under conditions of stress, most prominently after stimulation with the pro-inflammatory cytokine tumor necrosis factor a, in a manner dependent on nuclear factor kappa-light-chain-enhancer of activated B cells (NFjB). We found that NFjB signaling is activated in human breast cancer tissue, which was accompanied by an increase in NCS1 mRNA expression. Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca 2+ levels, and decreased inositol 1,4,5-trisphosphate-mediated Ca 2+ responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca 2+ . Conversely, Akt activity was increased in cells overexpressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up-regulated by stress-induced NFjB signaling and that NCS1 influences cell survival and motility through effects on Ca 2+ signaling and Akt pathway activation. AbbreviationsAkt, protein kinase B; Ca 2+ , calcium; ER, endoplasmic reticulum; InsP3, inositol 1,4,5-trisphosphate; InsP3R, inositol 1,4,5-trisphosphate receptor; IjBa, nuclear factor of kappa-light polypeptide gene enhancer in B-cell inhibition, alpha; NCS1, neuronal calcium sensor 1; NFjB, nuclear factor kappa-light-chain-enhancer of activated B cells; p-Akt, phosphorylated Akt; PI3K, phosphoinositide-3-kinase; PP2Ac, catalytic subunit of protein phosphatase 2A; tBHP, tert-butylhydroperoxide; TG, thapsigargin; TNF-a, tumor necrosis factor alpha.

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Section: Ncs1 Ko Renders Cells Deficient In Colony Formation and Migr...supporting

confidence: 87%

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

et al. 2020

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“…Two variants of NCS-1 (frq1 and frq2) are expressed in Drosophila (Sanchez-Gracia et al 2010) and may have distinct roles. A second human variant has been described but it is likely not to play any physiological role being expressed at only low levels (Wang et al 2016).…”

Section: The Physiology and Function Of Ncs Proteinsmentioning

confidence: 99%

Calcium Sensors in Neuronal Function and Dysfunction

Burgoyne

Helassa

McCue

et al. 2019

Cold Spring Harb Perspect Biol

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Calcium signaling in neurons as in other cell types can lead to varied changes in cellular function. Neuronal Ca 2+ signaling processes have also become adapted to modulate the function of specific pathways over a wide variety of time domains and these can have effects on, for example, axon outgrowth, neuronal survival, and changes in synaptic strength. Ca 2+ also plays a key role in synapses as the trigger for fast neurotransmitter release. Given its physiological importance, abnormalities in neuronal Ca 2+ signaling potentially underlie many different neurological and neurodegenerative diseases. The mechanisms by which changes in intracellular Ca 2+ concentration in neurons can bring about diverse responses is underpinned by the roles of ubiquitous or specialized neuronal Ca 2+ sensors. It has been established that synaptotagmins have key functions in neurotransmitter release, and, in addition to calmodulin, other families of EF-hand-containing neuronal Ca 2+ sensors, including the neuronal calcium sensor (NCS) and the calcium-binding protein (CaBP) families, play important physiological roles in neuronal Ca 2+ signaling. It has become increasingly apparent that these various Ca 2+ sensors may also be crucial for aspects of neuronal dysfunction and disease either indirectly or directly as a direct consequence of genetic variation or mutations. An understanding of the molecular basis for the regulation of the targets of the Ca 2+ sensors and the physiological roles of each protein in identified neurons may contribute to future approaches to the development of treatments for a variety of human neuronal disorders.C alcium signaling in many cell types can mediate a diverse range of changes in cellular function affecting gene expression, cell growth, development, survival, and cell death. In addition, neuronal calcium signaling processes have become adapted to modulate the function of other important pathways in the brain, including neuronal survival, axon outgrowth (Spitzer 2006), and changes in synaptic strength (Catterall and Few 2008;Catterall et al. 2013).Changes in the concentration of intracellular free Ca 2+ ([Ca 2+ ] i ) are essential for the transmission of information through the nervous system as the trigger for neurotransmitter release at synapses. In addition, alterations in [Ca 2+ ] i can lead to a wide variety of different physiological changes that can modify neuronal functions over a range of time domains of milliseconds through 10 sec, to minutes to days or longer (Berridge 1998). It has long been believed that

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“…Similarly, a second variant of NCS-1 was identified in humans from RNA screens where the N-terminal 22 amino acids are lacking which results in altered Ca 2+ binding. This variant does not appear to be expressed and no functional role was found [34].…”

Section: Ncs-1 Properties and Molecular Functionsmentioning

confidence: 99%

NCS-1 is a regulator of calcium signaling in health and disease

Boeckel

Ehrlich

2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Neuronal Calcium Sensor-1 (NCS-1) is a highly conserved calcium binding protein which contributes to the maintenance of intracellular calcium homeostasis and regulation of calcium-dependent signaling pathways. It is involved in a variety of physiological cell functions, including exocytosis, regulation of calcium permeable channels, neuroplasticity and response to neuronal damage. Over the past 30 years, continuing investigation of cellular functions of NCS-1 and associated disease states have highlighted its function in the pathophysiology of several disorders and as a therapeutic target. Among the diseases that were found to be associated with NCS-1 are neurological disorders such as bipolar disease and non-neurological conditions such as breast cancer. Furthermore, alteration of NCS-1 expression is associated with substance abuse disorders and severe side effects of chemotherapeutic agents. The objective of this article is to summarize the current body of evidence describing NCS-1 and its interactions on a molecular and cellular scale, as well as describing macroscopic implications in physiology and medicine. Particular attention is paid to the role of NCS-1 in development and prevention of chemotherapy induced peripheral neuropathy (CIPN).

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Neuronal Calcium Sensor 1 Has Two Variants with Distinct Calcium Binding Characteristics

Cited by 12 publications

References 30 publications

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

Calcium Sensors in Neuronal Function and Dysfunction

NCS-1 is a regulator of calcium signaling in health and disease

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