Gene Regulation Of α4β2 Nicotinic Receptors: Microarray Analysis Of Nicotine-Induced Receptor Up-Regulation And Anti-Inflammatory Effects

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Journal Title, Volume, Page: 
Journal of Neurochemistry Volume 111, Issue 3, pages 848–858, November 2009
Year of Publication: 
2009
Authors: 
Vishnu Hosur
Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts, USA
Scott Leppanen
Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts, USA
Adham Abutaha
Faculty of Pharmacy, An-Najah National University, Nablus, Palestine
Ralph H. Loring
Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts, USA
Preferred Abstract (Original): 

α4β2 Nicotinic acetylcholine receptors play an important role in the reward pathways for nicotine. We investigated whether receptor up-regulation of α4β2 nicotinic acetylcholine receptors involves expression changes for non-receptor genes. In a microarray analysis, 10 μM nicotine altered expression of 41 genes at 0.25, 1, 8 and 24 h in hα4β2 SH-EP1 cells. The maximum number of gene changes occurred at 8 h, around the initial increase in 3[H]-cytisine binding. Quantitative RT-PCR corroborated gene induction of endoplasmic reticulum proteins CRELD2, PDIA6, and HERPUD1, and suppression of the pro-inflammatory cytokines IL-1β and IL-6. Nicotine suppresses IL-1β and IL-6 expression at least in part by inhibiting NFκB activation. Antagonists dihydro-β-erythroidine and mecamylamine blocked these nicotine-induced changes showing that receptor activation is required. Antagonists alone or in combination with nicotine suppressed CRELD2 message while increasing α4β2 binding. Additionally, small interfering RNA knockdown of CRELD2 increased basal α4β2 receptor expression, and antagonists decreased CRELD2 expression even in the absence of α4β2 receptors. These data suggest that endoplasmic reticulum proteins such as CRELD2 can regulate α4β2 expression, and may explain antagonist actions in nicotine-induced receptor up-regulation. Further, the unexpected finding that nicotine suppresses inflammatory cytokines suggests that nicotinic α4β2 receptor activation promotes anti-inflammatory effects similar to α7 receptor activation.

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