CD38 is a bifunctional ectoenzyme, predominantly expressed on hematopoietic cells during differentiation, that catalyzes the synthesis (cyclase) and the degradation (hydrolase) of cyclic ADP-ribose (cADPR), a powerful calcium mobilizer from intracellular stores. Due to the well established role of calcium levels in the regulation of apoptosis, proliferation, and differentiation, the CD38/cADPR system seems to be a likely candidate involved in the control of these fundamental processes. The ectocellular localization of the cyclase activity, however, contrasts with the intracellular site of action of cADPR. Here we demonstrate that ectocellular expression of human CD38 in CD38⁻ HeLa and 3T3 cells results in intracellular CD38 substrate (NAD⁺ + NADH) consumption and product (cADPR) accumulation. Furthermore, a causal relationship is established between presence of intracellular cADPR, partial depletion of thapsigargin-sensitive calcium stores, increase in basal free cytoplasmic calcium concentration, and decrease of cell doubling time. The significant shortening of the S phase in CD38⁺ HeLa cells, as compared with controls, demonstrates an effect of intracellular cADPR on the mammalian cell cycle.

The role of voltage-dependent Ca channels (VDCC) in the membrane permeation of two toxic metals, lead (Pb) and cadmium (Cd), was studied in mammalian cells. Both metals interact with Ca-binding sites, but, while Cd influx appears to occur mainly through the same pathways as Ca, Pb is also rapidly taken up by different passive transport systems. Furthermore, I compared the effect of Cd in two Chinese hamster ovary (CHO) cell lines, a wild-type and a modified cell line, which were permanently transfected with an L-type VDCC. When cultures were subjected to a brief (30–60 min) exposure to 50–100 μM Cd, apoptotic features, metal accumulation, and death were comparable in both cell lines although, in transfected cells, the effect of Cd treatment was partially prevented by nimodipine (VDCC antagonist) and enhanced by BayK8644 (VDCC agonist). Thus, expression of L-type Ca channels is not sufficient to modify Cd accumulation and sensitivity to a toxicological significant extent and while both Cd and Pb can take advantage of VDCC to permeate the membrane, these transport proteins are not the only, and frequently not the most important, pathways of permeation.