CDN1163, a SERCA activator, causes intracellular Ca2+ leak, mitochondrial hyperpolarization and cell cycle arrest in mouse neuronal N2A cells

Huang, Yiping; Huang, Wen Wen; Tsai, Kun-Feng; Shiao, Lian‐Ru; Yang, Zhouxin; Tseng, Szu-Wen; Lin, Yu‐Hsien; Chen, Cing‐Yu; Chan, Paul; Leung, Yuk‐Man

doi:10.1016/j.neuro.2023.07.001

Cited by 2 publications

(2 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, SERCA is a key protein responsible for maintaining calcium homeostasis and initiating muscle relaxation by transporting cytoplasmic calcium to the SR lumen 34 . The impairment of SERCA function can affect calcium homeostasis, leading to the occurrence of diseases 35 . Therefore, molecules targeting SERCA may become a new class of insecticides.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Establishment and evaluation of targeted molecular screening model for the ryanodine receptor or sarco/endoplasmic reticulum calcium ATPase

Lu,

Jiang,

Chen

et al. 2024

Pest Management Science

View full text Add to dashboard Cite

BACKGROUDEndoplasmic reticulum/sarcoplasmic reticulum (ER/SR) is crucial for maintaining intracellular calcium homeostasis due to the calcium‐signaling‐related proteins on its membrane. While ryanodine receptors (RyR) on insect ER/SR membranes are well‐known as targets for diamide insecticides, little is known about other calcium channels. Given the resistance of diamide insecticides, the establishment of molecular screening models targeting RyR or sarco/endoplasmic reticulum calcium ATPase (SERCA) is conducive to the discovery of new insecticidal molecules.RESULTSThe morphological features of Mythimna separata SR have closed vesicles with integrity and high density. The 282 proteins in the SR component contained RyR and SERCA. A measurement model for the release and uptake of calcium was successfully established by detecting calcium ions outside the SR membrane using a fluorescence spectrophotometer. In vitro testing systems using SR vesicles found that diamide insecticides could activate dose‐dependently RyR, with EC50 values of 0.14 μM (Chlorantraniliprole), 0.21 μM (Flubendiamide), and 0.57 μM (Cyantraniliprole), respectively. However, dantrolene inhibited RyR‐mediated calcium release with an IC50 value of 353.9 μM, suggesting that dantrolene can weakly antagonize RyR. Moreover, cyclopiazonic acid significantly reduced the enzyme activity and calcium uptake capacity of SERCA. On the contrary, CDN1163 markedly activated the enzyme activity and improved the calcium transport capacity of SERCA.CONCLUSIONSSR vesicles can be used to study the function of unknown proteins on the SR membranes, as well as for high‐throughput screening of highly active compounds targeting RyR or SERCA.This article is protected by copyright. All rights reserved.

show abstract

Section: Discussionmentioning

confidence: 99%

“…34 The impairment of SERCA function can affect calcium homeostasis, leading to the occurrence of diseases. 35 Therefore, molecules targeting SERCA may become a new class of insecticides. However, a selective evaluation of molecules targeting SERCA, such as between mammals and insects, is needed.…”

Section: Discussionmentioning

confidence: 99%

Establishment and evaluation of targeted molecular screening model for the ryanodine receptor or sarco/endoplasmic reticulum calcium ATPase

Lu,

Jiang,

Chen

et al. 2024

Pest Management Science

View full text Add to dashboard Cite

show abstract

SERCA Modulators Reveal Distinct Signaling and Functional Roles of T Lymphocyte Ca2+ Stores

Uddin,

Thomas

2024

IJMS

View full text Add to dashboard Cite

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low-dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0–30 min) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA-3 regulated store, given the observation of increased Ca2+ release inducible by low-dose tBHQ. Intriguingly, longer-term (>12 h) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools yet decreased Ca2+ release responses from the tBHQ-sensitive SERCA 3 pool. Indeed, this remodeling of SERCA 2b Ca2+ stores with longer-term CDN1163 exposure also translated into the compound’s ability to protect Jurkat T lymphocytes from TG but not tBHQ-induced growth suppression.

show abstract

CDN1163, a SERCA activator, causes intracellular Ca2+ leak, mitochondrial hyperpolarization and cell cycle arrest in mouse neuronal N2A cells

Cited by 2 publications

References 28 publications

Establishment and evaluation of targeted molecular screening model for the ryanodine receptor or sarco/endoplasmic reticulum calcium ATPase

Establishment and evaluation of targeted molecular screening model for the ryanodine receptor or sarco/endoplasmic reticulum calcium ATPase

SERCA Modulators Reveal Distinct Signaling and Functional Roles of T Lymphocyte Ca2+ Stores

Contact Info

Product

Resources

About