Adenine Dinucleotide Second Messengers and T-lymphocyte Calcium Signaling

Abstract

Calcium signaling is a universal signal transduction mechanism in animal and plant cells. In mammalian T-lymphocytes calcium signaling is essential for activation and re-activation and thus important for a functional immune response. Since many years it has been known that both calcium release from intracellular stores and calcium entry via plasma membrane calcium channels are involved in shaping spatio-temporal calcium signals. Second messengers derived from the adenine dinucleotides NAD and NADP have been implicated in T cell calcium signaling. Nicotinic acid adenine dinucleotide phosphate (NAADP) acts as a very early second messenger upon T cell receptor/CD3 engagement, while cyclic ADP-ribose (cADPR) is mainly involved in sustained partial depletion of the endoplasmic reticulum by stimulating calcium release via ryanodine receptors. Finally, adenosine diphosphoribose (ADPR) a breakdown product of both NAD and cADPR activates a plasma membrane cation channel termed TRPM2 thereby facilitating calcium (and sodium) entry into T cells. Receptor-mediated formation, metabolism, and mode of action of these novel second messengers in T-lymphocytes will be reviewed.

Keywords: T-lymphocyte; TRPM2 cation channels; adenosine diphosphoribose; calcium entry; calcium release; calcium signaling; cyclic ADP-ribose; nicotinic acid adenine dinucleotide phosphate.

Figure 1

Metabolism of adenine derived second messengers cADPR, NAADP, and ADPR.

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.