CD38/cADPR/Ca2+ Pathway Promotes Cell Proliferation and Delays Nerve Growth Factor-induced Differentiation in PC12 Cells

Jianbo Yue,Wenjie Wei,Connie M.C Lam,Yong-Juan Zhao,Min Dong,Liang-Ren Zhang,Li-He Zhang,Hon-Cheung Lee

doi:10.1074/jbc.m109.049767

Jianbo Yue, Wenjie Wei + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m109.049767

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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.

Highlights

Ample evidence shows that the ryanodine receptors are the main intracellular targets for cyclic adenosine diphosphoribose (cADPR) [1, 2, 8]
The type 2 ryanodine receptor is expressed in PC12 cells and activation of the NO/cGMP pathway in PC12 cells results in calcium mobilization, which is mediated by cADPR and similar to that seen in sea urchin eggs [32]
To test the possible role of cADPR in proliferation and differentiation in PC12 cells, we first examined the expression of CD38 and type 2 ryanodine receptors (RyR2) in PC12 cells by RT-PCR and immunoblot analysis

Summary

Introduction

Ample evidence shows that the ryanodine receptors are the main intracellular targets for cADPR [1, 2, 8]. We show that activation of the CD38/cADPR/Ca2ϩ signaling is required for the ACh-induced proliferation in PC12 cells, while inhibition of the pathway accelerates NGF-induced neuronal differentiation. To test the possible role of cADPR in proliferation and differentiation in PC12 cells, we first examined the expression of CD38 and type 2 ryanodine receptors (RyR2) in PC12 cells by RT-PCR and immunoblot analysis.

Results

Conclusion