CD38/cADPR/Ca 2+ pathway promotes cell proliferation and delays nerve growth factor-induced differentiation in PC12 cells

Abstract

Intracellular Ca 2+ mobilization plays an important role in a wide variety of cellular processes, and multiple second messengers are responsible for mediating intracellular Ca 2+ changes. Here we explored the role of one endogenous Ca 2+ -mobilizing nucleotide, cyclic adenosine diphosphoribose (cADPR), in the proliferation and differentiation of neurosecretory PC12 cells. We found that cADPR induced Ca 2+ release in PC12 cells and that CD38 is the main ADP-ribosyl cyclase responsible for the acetylcholine (ACh)-induced cADPR production in PC12 cells. In addition, the CD38/ cADPR signaling pathway is shown to be required for the ACh-induced Ca 2+ increase and cell proliferation. Inhibition of the pathway, on the other hand, accelerated nerve growth factor (NGF)-induced neuronal differentiation in PC12 cells. Conversely, overexpression of CD38 increased cell proliferation but delayed NGF-induced differentiation. Our data indicate that cADPR plays a dichotomic role in regulating proliferation and neuronal differentiation of PC12 cells. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.