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

Authors

• Md N. Uddin, University of the PacificFollow
• David W. Thomas, University of the PacificFollow

Document Type

Article

Publication Title

International Journal of Molecular Sciences

Department

Pharmacy

ISSN

14220067

Volume

25

Issue

22

DOI

10.3390/ijms252212095

First Page

1

Last Page

25

Publication Date

11-11-2024

Abstract

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.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Uddin, Md N. and Thomas, David W., "SERCA Modulators Reveal Distinct Signaling and Functional Roles of T Lymphocyte Ca2+ Stores" (2024). Pacific Faculty Work. 70.
https://scholarlycommons.pacific.edu/all-faculty/70