Biomaterial Database

Gene regulation of alpha4beta2 nicotinic receptors: microarray analysis of nicotine-induced receptor up-regulation and anti-inflammatory effects. 2009

Vishnu Hosur, and Scott Leppanen, and Adham Abutaha, and Ralph H Loring

Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts, USA.

alpha4beta2 Nicotinic acetylcholine receptors play an important role in the reward pathways for nicotine. We investigated whether receptor up-regulation of alpha4beta2 nicotinic acetylcholine receptors involves expression changes for non-receptor genes. In a microarray analysis, 10 muM nicotine altered expression of 41 genes at 0.25, 1, 8 and 24 h in halpha4beta2 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-1beta and IL-6. Nicotine suppresses IL-1beta and IL-6 expression at least in part by inhibiting NFkappaB activation. Antagonists dihydro-beta-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 alpha4beta2 binding. Additionally, small interfering RNA knockdown of CRELD2 increased basal alpha4beta2 receptor expression, and antagonists decreased CRELD2 expression even in the absence of alpha4beta2 receptors. These data suggest that endoplasmic reticulum proteins such as CRELD2 can regulate alpha4beta2 expression, and may explain antagonist actions in nicotine-induced receptor up-regulation. Further, the unexpected finding that nicotine suppresses inflammatory cytokines suggests that nicotinic alpha4beta2 receptor activation promotes anti-inflammatory effects similar to alpha7 receptor activation.

UI	MeSH Term	Description	Entries
D008565	Membrane Proteins	Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.	Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D009447	Neuroblastoma	A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51)	Neuroblastomas
D009538	Nicotine	Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke.	Nicotine Bitartrate,Nicotine Tartrate
D011807	Quinolizines
D011978	Receptors, Nicotinic	One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for NICOTINE over MUSCARINE. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, and subunit composition of the receptors.	Nicotinic Acetylcholine Receptors,Nicotinic Receptors,Nicotinic Acetylcholine Receptor,Nicotinic Receptor,Acetylcholine Receptor, Nicotinic,Acetylcholine Receptors, Nicotinic,Receptor, Nicotinic,Receptor, Nicotinic Acetylcholine,Receptors, Nicotinic Acetylcholine
D005786	Gene Expression Regulation	Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.	Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000097782	NF-kappaB-Inducing Kinase	A protein serine-threonine kinase that catalyzes the activation of canonical and non-canonical NF-kappaB pathways.	MAP3K14 Kinase,Mitogen-Activated Protein Kinase Kinase Kinase 14,NF-kappa B Kinase,NF-kappa-B-Inducing Kinase (NIK),NFkB Kinase,NIK Protein,Nuclear Factor kappa B Kinase,B Kinase, NF-kappa,Kinase, MAP3K14,Kinase, NF-kappa B,Kinase, NF-kappaB-Inducing,Kinase, NFkB,Mitogen Activated Protein Kinase Kinase Kinase 14,NF kappa B Kinase,NF kappaB Inducing Kinase,Protein, NIK
D000470	Alkaloids	Organic nitrogenous bases. Many alkaloids of medical importance occur in the animal and vegetable kingdoms, and some have been synthesized. (Grant & Hackh's Chemical Dictionary, 5th ed)	Alkaloid,Plant Alkaloid,Plant Alkaloids,Alkaloid, Plant,Alkaloids, Plant
D000704	Analysis of Variance	A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable.	ANOVA,Analysis, Variance,Variance Analysis,Analyses, Variance,Variance Analyses