NAD+ surfaces again

Abstract

NAD⁺ and its metabolites serve important functions in intracellular signalling. NAD⁺-mediated regulatory processes also take place on the cell surface, particularly of immune cells. In this issue of the Biochemical Journal, Gerth et al. have demonstrated a new mechanism of Ca²⁺ uptake into monocytes which is triggered by NAD⁺ or its degradation product, ADP-ribose. These observations point to a hitherto unknown Ca²⁺-influx mechanism and underscore the potential significance of NAD⁺ and ADP-ribose as signalling molecules on the extracellular side of the plasma membrane.

Figure 1. NAD⁺ and its derivatives as intra- and extra-cellular Ca²⁺-mobilizing molecules

As well as serving as a substrate for ARTs, extracellular NAD⁺ converted into cADPR by membrane-associated CD38 might elicit Ca²⁺ release from intracellular stores following uptake into the cell. The same mechanism is supposed to be activated by cADPR generated by yet uncharacterized ADP-ribosyl cyclase(s) within the cell. Ca²⁺ entry from the extracellular fluid may be triggered by intracellular NAD⁺ and its derivative, ADPR, by acting on TRPM2. In this issue of the Biochemical Journal Gerth et al. [7] propose a similar mechanism, however, triggered by extracellular NAD⁺ or ADPR operating on a different, still to be identified, ligand-gated Ca²⁺ channel.