FIGURE 4.

Emerging mechanisms of regulating the signaling function of CD38. NAADP activates the TPCs in the endolysosomes (Ly), whereas cADPR targets the ryanodine receptors (RyR) in the ER. Ca²⁺ released by NAADP from the endolysosomal stores can be amplified Ca²⁺-induced Ca²⁺ release from ER stores. This process is potentiated by cADPR through its sensitization of the ryanodine receptors to Ca²⁺. CD38 can be coexpressed with both type II and III membrane orientations. Type II CD38 has its catalytic domain facing either outside of the cell or inside the lumen of organelles. Regulation of type II CD38 is proposed to be through substrate limitation, as both NAD and NADP are in the cytosol. Their transport into the organelles is mediated by connexin-43 (Cnx), whereas the products cADPR and NAADP, produced in the lumen, can likewise be transported out to the cytosol by the nucleoside transporters (NuT). Both nucleoside transporters and connexin-43 are also present on the cell surface to serve a similar function for signaling by the ecto-expressed CD38. Type III CD38 is amenable to many common regulation mechanisms, such as phosphorylation.