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

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase (SERCA) activators are emerging pharmacological tools.
• CDN1163 is a novel allosteric SERCA activator.
• Understanding its effects on T lymphocyte calcium signaling is crucial.

Purpose of the Study:

• To investigate the effects of CDN1163 on calcium (Ca2+) stores in Jurkat T lymphocytes.
• To determine the isoform-specific actions of CDN1163 on SERCA 2b and SERCA 3.
• To examine the time-dependent and concentration-dependent effects of CDN1163.

Main Methods:

• Utilized Jurkat T lymphocytes as a model system for Ca2+ signaling.
• Established low-dose SERCA inhibitor regimens (thapsigargin and tBHQ) to differentiate SERCA 2b and SERCA 3 stores.
• Assessed Ca2+ release and uptake dynamics following short-term (0-30 min) and long-term (>12 h) CDN1163 exposure.

Main Results:

• Short-term CDN1163 exposure suppressed Ca2+ uptake and diminished Ca2+ release from SERCA 2b stores.
• Short-term CDN1163 demonstrated a SERCA-activating effect on SERCA 3 stores, increasing Ca2+ release.
• Long-term CDN1163 exposure reversed these effects, increasing Ca2+ release from SERCA 2b and decreasing it from SERCA 3 stores, conferring protection against thapsigargin-induced growth suppression.

Conclusions:

• CDN1163 exhibits complex, time-sensitive, and SERCA isoform-specific modulation of T lymphocyte Ca2+ stores.
• The compound's effects differ significantly between short-term and long-term exposure.
• Long-term CDN1163 treatment remodels Ca2+ stores and impacts T lymphocyte viability.