Open AccessCD38/Cyclic ADP-Ribose Regulates Astrocyte Calcium Signaling: Implications for Neuroinflammation and HIV-1-Associated Dementia
Author(s) -
Sugato Banerjee,
Timothy F. Walseth,
Kathleen Borgmann,
Li Wu,
Keshore R. Bidasee,
Mathur Kannan,
Anuja Ghorpade
Publication year - 2008
Publication title -
journal of neuroimmune pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.219
H-Index - 70
eISSN - 1557-1904
pISSN - 1557-1890
DOI - 10.1007/s11481-008-9105-7
Subject(s) - cd38 , cyclic adp ribose , astrocyte , neuroinflammation , microbiology and biotechnology , calcium in biology , chemistry , biochemistry , biology , intracellular , immunology , endocrinology , inflammation , stem cell , cd34 , central nervous system
CD38 is a 45-kD ectoenzyme involved in the synthesis of potent calcium (Ca(2+))-mobilizing agents, cyclic adenosine diphosphate-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP+). In HIV-1-infected patients, increased CD38 expression on CD8+ T cells is linked to immune system activation and progression of HIV-1 infection. However, the role of CD38 upregulation in astrocyte function and HIV-1-associated dementia (HAD-now called HAND: HIV-1-associated neurocognitive disorder) neuropathogenesis is unclear. To these ends, we used interleukin (IL)-1beta and HIV-1gp120 to activate primary human astrocytes and measured CD38 expression using real-time polymerase chain reaction and CD38 function by ADP-ribosyl cyclase activity. We also determined cADPR-mediated changes in single-cell intracellular Ca(2+) transients in activated astrocytes in presence or absence of ethylene glycol tetraacetic acid. CD38 levels were downregulated using CD38 small-interfering RNA (siRNA) and intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured. We previously reported a approximately 20-fold rise in CD38 messenger RNA levels in IL-1beta-activated astrocytes. We extend this observation and report that HIV-1gp120 potentiated CD38 expression in a dose-dependent manner and also increased CD38 enzyme activity in control and IL-1beta-activated astrocytes. We demonstrate higher cADPR levels in IL-1beta-activated astrocytes with a corresponding rise in [Ca(2+)](i) upon cADPR application and its non-hydrolysable analog, 3-deaza-cADPR. In activated astrocytes, pre-treatment with the cADPR-specific antagonist 8-Br-cADPR and CD38 siRNA transfection returned elevated [Ca(2+)](i) to baseline, thus confirming a CD38-cADPR specific response. These data are important for unraveling the mechanisms underlying the role of astrocyte-CD38 in HAD and have broader implications in other inflammatory diseases involving astrocyte activation and CD38 dysregulation.