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SERCA Modulators Reveal Distinct Signaling and Functional Roles of T Lymphocyte Casup.2+ Stores
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Journal Article
SERCA Modulators Reveal Distinct Signaling and Functional Roles of T Lymphocyte Casup.2+ Stores
2024
Overview
The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca[sup.2+] -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 Ca[sup.2+] stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca[sup.2+] 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 Ca[sup.2+] , permitting the differentiation of the TG-sensitive SERCA 2b Ca[sup.2+] store from the tBHQ-sensitive SERCA 3 Ca[sup.2+] store. We proceeded to test the effects of CDN1163 on Ca[sup.2+] stores, examining specific actions on the SERCA 2b and SERCA 3 Ca[sup.2+] 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 Ca[sup.2+] stores. Surprisingly, short-term exposure (0–30 min) to CDN1163 perturbs T cell Ca[sup.2+] stores by suppressing Ca[sup.2+] uptake with diminished Ca[sup.2+] 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 Ca[sup.2+] release inducible by low-dose tBHQ. Intriguingly, longer-term (>12 h) CDN1163 exposure reversed this pattern, with increased Ca[sup.2+] release from SERCA 2b-regulated pools yet decreased Ca[sup.2+] release responses from the tBHQ-sensitive SERCA 3 pool. Indeed, this remodeling of SERCA 2b Ca[sup.2+] 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.
Publisher
MDPI AG
Subject
