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Article: Nicotinic acetylcholine receptors mediate lung cancer growth.

Improgo, Ma Reina / Soll, Lindsey G / Tapper, Andrew R / Gardner, Paul D

2013 Volume 4, Page(s) 251

Abstract: Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport-vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, ... ...

Abstract	Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport-vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC), the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an α3β4-selective antagonist, α-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via α3/α5/β4-containing nAChRs promotes lung carcinogenesis.
Language	English
Publishing date	2013-09-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2013.00251
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Article ; Online: Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer.

Improgo, Ma Reina / Tapper, Andrew R / Gardner, Paul D

Biochemical pharmacology

2011 Volume 82, Issue 8, Page(s) 1015–1021

Abstract: Despite the known adverse health effects associated with tobacco use, over 45 million adults in the United States smoke. Cigarette smoking is the major etiologic factor associated with lung cancer. Cigarettes contain thousands of toxic chemicals, many of ...

Abstract	Despite the known adverse health effects associated with tobacco use, over 45 million adults in the United States smoke. Cigarette smoking is the major etiologic factor associated with lung cancer. Cigarettes contain thousands of toxic chemicals, many of which are carcinogenic. Nicotine contributes directly to lung carcinogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels, expressed in both normal and lung cancer cells, which mediate the proliferative, pro-survival, angiogenic, and metastatic effects of nicotine and its nitrosamine derivatives. The underlying molecular mechanisms involve increases in intracellular calcium levels and activation of cancer signal transduction pathways. In addition, acetylcholine (ACh) acts as an autocrine or paracrine growth factor in lung cancer. Other neurotransmitters and neuropeptides also activate similar growth loops. Recent genetic studies further support a role for nAChRs in the development of lung cancer. Several nAChR antagonists have been shown to inhibit lung cancer growth, suggesting that nAChRs may serve as valuable targets for biomarker-guided lung cancer interventions.
MeSH term(s)	Animals ; Autocrine Communication ; Calcium/metabolism ; Cell Proliferation/drug effects ; Humans ; Lung/drug effects ; Lung/metabolism ; Lung/pathology ; Lung Neoplasms/blood supply ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Lung Neoplasms/prevention & control ; Nicotine/toxicity ; Nicotinic Antagonists/therapeutic use ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Signal Transduction
Chemical Substances	Nicotinic Antagonists ; Receptors, Nicotinic ; Nicotine (6M3C89ZY6R) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2011-10-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2011.05.020
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Article ; Online: High-Throughput Quantitative Assay Technologies for Accelerating the Discovery and Optimization of Targeted Protein Degradation Therapeutics.

Simard, Jeffrey R / Lee, Linda / Vieux, Ellen / Improgo, Reina / Tieu, Trang / Phillips, Andrew J / Fisher, Stewart L / Pollock, Roy M / Park, Eunice

SLAS discovery : advancing life sciences R & D

2021 Volume 26, Issue 4, Page(s) 503–517

Abstract: The aberrant regulation of protein expression and function can drastically alter cellular physiology and lead to numerous pathophysiological conditions such as cancer, inflammatory diseases, and neurodegeneration. The steady-state expression levels of ... ...

Abstract	The aberrant regulation of protein expression and function can drastically alter cellular physiology and lead to numerous pathophysiological conditions such as cancer, inflammatory diseases, and neurodegeneration. The steady-state expression levels of endogenous proteins are controlled by a balance of de novo synthesis rates and degradation rates. Moreover, the levels of activated proteins in signaling cascades can be further modulated by a variety of posttranslational modifications and protein-protein interactions. The field of targeted protein degradation is an emerging area for drug discovery in which small molecules are used to recruit E3 ubiquitin ligases to catalyze the ubiquitination and subsequent degradation of disease-causing target proteins by the proteasome in both a dose- and time-dependent manner. Traditional approaches for quantifying protein level changes in cells, such as Western blots, are typically low throughput with limited quantification, making it hard to drive the rapid development of therapeutics that induce selective, rapid, and sustained protein degradation. In the last decade, a number of techniques and technologies have emerged that have helped to accelerate targeted protein degradation drug discovery efforts, including the use of fluorescent protein fusions and reporter tags, flow cytometry, time-resolved fluorescence energy transfer (TR-FRET), and split luciferase systems. Here we discuss the advantages and disadvantages associated with these technologies and their application to the development and optimization of degraders as therapeutics.
MeSH term(s)	Drug Discovery/methods ; Eukaryotic Cells/cytology ; Eukaryotic Cells/drug effects ; Eukaryotic Cells/metabolism ; Flow Cytometry/methods ; High-Throughput Screening Assays ; Humans ; Ligands ; Molecular Targeted Therapy/methods ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Processing, Post-Translational ; Proteolysis/drug effects ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Spectrometry, Fluorescence/methods ; Staining and Labeling/methods ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination/drug effects
Chemical Substances	Ligands ; Recombinant Fusion Proteins ; Small Molecule Libraries ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2885123-7
ISSN	2472-5560 ; 2472-5552
ISSN (online)	2472-5560
ISSN	2472-5552
DOI	10.1177/2472555220985049
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Article: Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer

Improgo, Ma. Reina / Tapper, Andrew R / Gardner, Paul D

Biochemical Pharmacology. 2011 Oct. 15, v. 82, no. 8

2011

Abstract	Despite the known adverse health effects associated with tobacco use, over 45 million adults in the United States smoke. Cigarette smoking is the major etiologic factor associated with lung cancer. Cigarettes contain thousands of toxic chemicals, many of which are carcinogenic. Nicotine contributes directly to lung carcinogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels, expressed in both normal and lung cancer cells, which mediate the proliferative, pro-survival, angiogenic, and metastatic effects of nicotine and its nitrosamine derivatives. The underlying molecular mechanisms involve increases in intracellular calcium levels and activation of cancer signal transduction pathways. In addition, acetylcholine (ACh) acts as an autocrine or paracrine growth factor in lung cancer. Other neurotransmitters and neuropeptides also activate similar growth loops. Recent genetic studies further support a role for nAChRs in the development of lung cancer. Several nAChR antagonists have been shown to inhibit lung cancer growth, suggesting that nAChRs may serve as valuable targets for biomarker-guided lung cancer interventions.
Keywords	acetylcholine ; adults ; adverse effects ; antagonists ; calcium ; carcinogenesis ; carcinogenicity ; cholinergic receptors ; cigarettes ; ion channels ; lung neoplasms ; metastasis ; neuropeptides ; neurotransmitters ; nicotine ; signal transduction ; smoke ; smoking (habit) ; toxic substances ; United States
Language	English
Dates of publication	2011-1015
Size	p. 1015-1021.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2011.05.020
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Bioluminescence-based high-throughput screen identifies pharmacological agents that target neurotransmitter signaling in small cell lung carcinoma.

Improgo, Ma Reina D / Johnson, Christopher W / Tapper, Andrew R / Gardner, Paul D

PloS one

2011 Volume 6, Issue 9, Page(s) e24132

Abstract: Background: Frontline treatment of small cell lung carcinoma (SCLC) relies heavily on chemotherapeutic agents and radiation therapy. Though SCLC patients respond well to initial cycles of chemotherapy, they eventually develop resistance. Identification ... ...

Abstract	Background: Frontline treatment of small cell lung carcinoma (SCLC) relies heavily on chemotherapeutic agents and radiation therapy. Though SCLC patients respond well to initial cycles of chemotherapy, they eventually develop resistance. Identification of novel therapies against SCLC is therefore imperative. Methods and findings: We have designed a bioluminescence-based cell viability assay for high-throughput screening of anti-SCLC agents. The assay was first validated via standard pharmacological agents and RNA interference using two human SCLC cell lines. We then utilized the assay in a high-throughput screen using the LOPAC(1280) compound library. The screening identified several drugs that target classic cancer signaling pathways as well as neuroendocrine markers in SCLC. In particular, perturbation of dopaminergic and serotonergic signaling inhibits SCLC cell viability. Conclusions: The convergence of our pharmacological data with key SCLC pathway components reiterates the importance of neurotransmitter signaling in SCLC etiology and points to possible leads for drug development.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/pharmacology ; Dopamine Agents/pharmacology ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics ; HEK293 Cells ; Humans ; Luciferases/genetics ; Luciferases/metabolism ; Luminescent Measurements/methods ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Neurotransmitter Agents/metabolism ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Serotonin Agents/pharmacology ; Signal Transduction/drug effects ; Small Cell Lung Carcinoma/genetics ; Small Cell Lung Carcinoma/metabolism ; Small Cell Lung Carcinoma/pathology ; Staurosporine/pharmacology ; Time Factors
Chemical Substances	Antineoplastic Agents ; Dopamine Agents ; Neurotransmitter Agents ; Serotonin Agents ; Luciferases (EC 1.13.12.-) ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) (EC 1.2.1.12) ; Staurosporine (H88EPA0A3N) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2011-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0024132
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Article ; Online: The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer.

Improgo, Ma Reina D / Scofield, Michael D / Tapper, Andrew R / Gardner, Paul D

Progress in neurobiology

2010 Volume 92, Issue 2, Page(s) 212–226

Abstract: More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine ... ...

Abstract	More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine to nicotinic acetylcholine receptors, ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine. These receptors serve as prototypes for all ligand-gated ion channels and have been extensively studied in an attempt to elucidate their role in nicotine addiction. Many of these studies have focused on heteromeric nicotinic acetylcholine receptors containing α4 and β2 subunits and homomeric nicotinic acetylcholine receptors containing the α7 subunit, two of the most abundant subtypes expressed in the brain. Recently however, a series of linkage analyses, candidate-gene analyses and genome-wide association studies have brought attention to three other members of the nicotinic acetylcholine receptor family: the α5, α3 and β4 subunits. The genes encoding these subunits lie in a genomic cluster that contains variants associated with increased risk for several diseases including nicotine dependence and lung cancer. The underlying mechanisms for these associations have not yet been elucidated but decades of research on the nicotinic receptor gene family as well as emerging data provide insight on how these receptors may function in pathological states. Here, we review this body of work, focusing on the clustered nicotinic acetylcholine receptor genes and evaluating their role in nicotine addiction and lung cancer.
MeSH term(s)	Animals ; Genetic Predisposition to Disease/genetics ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Multigene Family/genetics ; Nerve Tissue Proteins/genetics ; Receptors, Nicotinic/genetics ; Tobacco Use Disorder/genetics ; Tobacco Use Disorder/metabolism
Chemical Substances	CHRNA5 protein, human ; CHRNB4 protein, human ; Nerve Tissue Proteins ; Receptors, Nicotinic ; nicotinic receptor subunit alpha3
Language	English
Publishing date	2010-06-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2010.05.003
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Article ; Online: Bioluminescence-based high-throughput screen identifies pharmacological agents that target neurotransmitter signaling in small cell lung carcinoma.

Ma Reina D Improgo / Christopher W Johnson / Andrew R Tapper / Paul D Gardner

PLoS ONE, Vol 6, Iss 9, p e

2011 Volume 24132

Abstract: BACKGROUND: Frontline treatment of small cell lung carcinoma (SCLC) relies heavily on chemotherapeutic agents and radiation therapy. Though SCLC patients respond well to initial cycles of chemotherapy, they eventually develop resistance. Identification ... ...

Abstract	BACKGROUND: Frontline treatment of small cell lung carcinoma (SCLC) relies heavily on chemotherapeutic agents and radiation therapy. Though SCLC patients respond well to initial cycles of chemotherapy, they eventually develop resistance. Identification of novel therapies against SCLC is therefore imperative. METHODS AND FINDINGS: We have designed a bioluminescence-based cell viability assay for high-throughput screening of anti-SCLC agents. The assay was first validated via standard pharmacological agents and RNA interference using two human SCLC cell lines. We then utilized the assay in a high-throughput screen using the LOPAC(1280) compound library. The screening identified several drugs that target classic cancer signaling pathways as well as neuroendocrine markers in SCLC. In particular, perturbation of dopaminergic and serotonergic signaling inhibits SCLC cell viability. CONCLUSIONS: The convergence of our pharmacological data with key SCLC pathway components reiterates the importance of neurotransmitter signaling in SCLC etiology and points to possible leads for drug development.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: MYD88 L265P mutations identify a prognostic gene expression signature and a pathway for targeted inhibition in CLL.

Improgo, Ma Reina / Tesar, Bethany / Klitgaard, Josephine L / Magori-Cohen, Reuma / Yu, Lijian / Kasar, Siddha / Chaudhary, Divya / Miao, Wenyan / Fernandes, Stacey M / Hoang, Kevin / Westlin, William F / Kim, Haesook T / Brown, Jennifer R

British journal of haematology

2018 Volume 184, Issue 6, Page(s) 925–936

Abstract: The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL ... ...

Abstract	The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL remains to be fully elucidated. Here, we report that MYD88 L265P mutations are associated with mutated immunoglobulin heavy-chain gene (IGHV-M) status and that among IGHV-M patients, the presence of MYD88 L265P is associated with younger age at diagnosis. Using microarray and RNA-Seq gene expression analysis, we further observe that the MYD88 L265P mutation is associated with a distinctive gene expression signature that predicts both failure-free survival and overall survival. This association was validated in an independent cohort of patients. To determine whether MYD88 L265P mutations can be therapeutically exploited in CLL, we treated primary cells with an inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), a critical effector of the MYD88 pathway. IRAK4 inhibition decreased downstream nuclear factor-κB signalling and cell viability in CLL cells, indicating the potential of the MYD88 pathway as a therapeutic target in CLL.
MeSH term(s)	Adult ; Aged ; Cohort Studies ; Cytokines/biosynthesis ; Female ; Genes, Immunoglobulin Heavy Chain ; Humans ; Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Male ; Middle Aged ; Molecular Targeted Therapy ; Mutation ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/metabolism ; Prognosis ; Signal Transduction ; Transcriptome
Chemical Substances	Cytokines ; MYD88 protein, human ; Myeloid Differentiation Factor 88 ; IRAK4 protein, human (EC 2.7.11.1) ; Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2018-12-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.15714
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Article ; Online: ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus.

Improgo, Ma Reina D / Schlichting, Nicolette A / Cortes, Roxana Y / Zhao-Shea, Rubing / Tapper, Andrew R / Gardner, Paul D

Molecular cancer research : MCR

2010 Volume 8, Issue 2, Page(s) 194–203

Abstract: Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have ... ...

Abstract	Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have implicated the nAChR gene cluster, CHRNA5/A3/B4, in nicotine addiction and lung cancer susceptibility. To further delineate the role of this gene cluster in lung cancer, we examined the expression levels of these three genes as well as other members of the nAChR gene family in lung cancer cell lines and patient samples using quantitative reverse transcription-PCR. Overexpression of the clustered nAChR genes was observed in small-cell lung carcinoma (SCLC), an aggressive form of lung cancer highly associated with cigarette smoking. The overexpression of the genomically clustered genes in SCLC suggests their coordinate regulation. In silico analysis of the promoter regions of these genes revealed putative binding sites in all three promoters for achaete-scute complex homolog 1 (ASCL1), a transcription factor implicated in the pathogenesis of SCLC, raising the possibility that this factor may regulate the expression of the clustered nAChR genes. Consistent with this idea, knockdown of ASCL1 in SCLC, but not in non-SCLC, led to a significant decrease in expression of the alpha 3 and beta 4 genes without having an effect on any other highly expressed nAChR gene. Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis.
MeSH term(s)	Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Binding Sites/genetics ; Carcinoma/genetics ; Carcinoma/metabolism ; Carcinoma/physiopathology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/physiopathology ; Multigene Family/genetics ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nicotine/adverse effects ; Promoter Regions, Genetic/genetics ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Receptors, Nicotinic/chemistry ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Small Cell Lung Carcinoma/genetics ; Small Cell Lung Carcinoma/metabolism ; Small Cell Lung Carcinoma/physiopathology ; Smoking/adverse effects ; Transcriptional Activation/genetics
Chemical Substances	ASCL1 protein, human ; Basic Helix-Loop-Helix Transcription Factors ; CHRNA5 protein, human ; CHRNB4 protein, human ; Nerve Tissue Proteins ; Protein Subunits ; Receptors, Nicotinic ; nicotinic receptor subunit alpha3 ; Nicotine (6M3C89ZY6R)
Language	English
Publishing date	2010-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-09-0185
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Article ; Online: Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area.

Zhao-Shea, Rubing / Liu, Liwang / Soll, Lindsey G / Improgo, Ma Reina / Meyers, Erin E / McIntosh, J Michael / Grady, Sharon R / Marks, Michael J / Gardner, Paul D / Tapper, Andrew R

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2011 Volume 36, Issue 5, Page(s) 1021–1032

Abstract: Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. In this study, we show that rewarding doses of nicotine ... ...

Abstract	Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. In this study, we show that rewarding doses of nicotine activated VTA DAergic neurons in a region-selective manner, preferentially activating neurons in the posterior VTA (pVTA) but not in the anterior VTA (aVTA) or in the tail VTA (tVTA). Nicotine (1 μM) directly activated pVTA DAergic neurons in adult mouse midbrain slices, but had little effect on DAergic neurons within the aVTA. Quantification of nAChR subunit gene expression revealed that pVTA DAergic neurons expressed higher levels of α4, α6, and β3 transcripts than did aVTA DAergic neurons. Activation of nAChRs containing the α4 subunit (α4() nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: nicotine failed to activate pVTA DAergic neurons in α4 knockout animals; in contrast, pVTA α4() nAChRs were selectively activated by nicotine in mutant mice expressing agonist-hypersensitive α4() nAChRs (Leu9'Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by α4() nAChRs and were significantly larger in pVTA neurons than in aVTA neurons. Infusion of an α6() nAChR antagonist into the VTA blocked activation of pVTA DAergic neurons in WT mice and in Leu9'Ala mice at nicotine doses, which only activate the mutant receptor indicating that α4 and α6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA through α4α6() nAChRs. These receptors represent novel targets for smoking-cessation therapies.
MeSH term(s)	6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Action Potentials/drug effects ; Analysis of Variance ; Animals ; Atropine/pharmacology ; Bicuculline/pharmacology ; Cell Count/methods ; Cell Size/drug effects ; Dopamine/metabolism ; Drug Interactions ; Electric Stimulation/methods ; Excitatory Amino Acid Antagonists/pharmacology ; GABA-A Receptor Antagonists/pharmacology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; In Vitro Techniques ; Male ; Mecamylamine/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microdissection/methods ; Muscarinic Antagonists/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Nicotine/pharmacology ; Nicotinic Agonists/pharmacology ; Nicotinic Antagonists/pharmacology ; Patch-Clamp Techniques/methods ; Proto-Oncogene Proteins c-fos/metabolism ; RNA, Messenger/metabolism ; Receptors, Nicotinic/deficiency ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Temperature ; Tyrosine 3-Monooxygenase/metabolism ; Ventral Tegmental Area/cytology
Chemical Substances	Excitatory Amino Acid Antagonists ; GABA-A Receptor Antagonists ; Muscarinic Antagonists ; Nicotinic Agonists ; Nicotinic Antagonists ; Proto-Oncogene Proteins c-fos ; RNA, Messenger ; Receptors, Nicotinic ; nicotinic acetylcholine receptor alpha4 subunit ; Mecamylamine (6EE945D3OK) ; Nicotine (6M3C89ZY6R) ; 6-Cyano-7-nitroquinoxaline-2,3-dione (6OTE87SCCW) ; Atropine (7C0697DR9I) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Dopamine (VTD58H1Z2X) ; Bicuculline (Y37615DVKC)
Language	English
Publishing date	2011-02-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/npp.2010.240
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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