Figure 2.

Model of T cell Ca²⁺ signaling. TCR/CD3 ligation by antigenic peptide presented by MHC molecules on antigen presenting cells results in consecutive formation of the second messengers NAADP, IP₃, and cADPR, all of which release Ca²⁺ from the ER. Thus, a continuously decreased intraluminal free Ca²⁺ concentration in the ER ([Ca²⁺]_lu) resulting from this constant Ca²⁺ release concomitantly activates CRAC/Orai1 channels in the plasma membrane. The mode of action of both NAADP and cADPR likely involves specific binding proteins for both second messengers (abbreviated here as NAADP-BP or cADPR-BP). A strong stimulus, e.g., cross-linking of receptors by concanavalin A (right side of Figure 2), triggers formation of ADPR and activation of TRPM2, in addition to the mechanisms described on the left side of the figure.