Journal
FASEB JOURNAL
Volume 16, Issue 3, Pages -Publisher
WILEY
DOI: 10.1096/fj.01-0705com
Keywords
endoplasmic reticulum; ryanodine receptor; myristoylation; osteoblasts
Categories
Funding
- NCI NIH HHS [CA 22762] Funding Source: Medline
- NIA NIH HHS [R01 AG14917-06] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA022762, R37CA022762] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG014917] Funding Source: NIH RePORTER
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CD38 is an ectocyclase that converts NAD(+) to the Ca2+ -releasing second messenger cyclic ADP- ribose (cADPr). Here we report that in addition to CD38 ecto- catalysis, intracellularly expressed CD38 may catalyze NAD(+) --> cADPr conversion to cause cytosolic Ca2+ release. High levels of CD38 were found in the plasma membranes, endoplasmic reticulum, and nuclear membranes of osteoblastic MC3T3- E1 cells. More important, intracellular CD38 was colocalized with target ryanodine receptors. The cyclase also converted a NAD(+) surrogate, NGD(+), to its fluorescent product, cGDPr (K-m similar to5.13 muM). NAD(+) also triggered a cytosolic Ca2+ signal. Similar results were obtained with NIH3T3 cells, which overexpressed a CD38- EGFP fusion protein. The Delta(-49) - CD38- EGFP mutant with a deleted amino- terminal tail and transmembrane domain appeared mainly in the mitochondria with an expected loss of its membrane localization, but the NAD(+) -induced cytosolic Ca2+ signal was preserved. Likewise, Ca2+ release persisted in cells transfected with the Myr-Delta(-49) -CD38- EGFP or Delta(-49) -CD38- EGFP- Fan mutants, both directed to the plasma membrane but in an opposite topology to the full- length CD38- EGFP. Finally, ryanodine inhibited Ca2+ signaling, indicating the downstream activation of ryanodine receptors by cADPr. We conclude that intracellularly expressed CD38 might link cellular NAD(+) production to cytosolic Ca2+ signaling.
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