Last update 01 Nov 2024

CHRNB2 x α4β2 receptor

Last update 01 Nov 2024

Basic Info

Related Targets

CHRNB2α4β2 receptor

Drugs associated with CHRNB2 x α4β2 receptor

[123] 5-I-A-85380

Target

CHRNB2 x α4β2 receptor

Mechanism

CHRNB2 modulators [+2]

Active Org.-

Originator Org.-

Active Indication-

Inactive Indication

Parkinson Disease [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with CHRNB2 x α4β2 receptor

NCT00397696 / CompletedPhase 2IIT

Evaluation of 5-[123I]-A-85380 and SPECT Imaging as a Marker of Nicotinic Receptor Density in the Brain of Parkinson Disease Subjects

The underlying goal of this study is to assess [123I] 5-IA and SPECT imaging as a tool to detect nicotinic receptor activity in the brain of PD patients. All study procedures will be conducted at the Institute for Neurodegenerative Disorders (IND) and Molecular NeuroImaging (MNI) in New Haven, CT. Approximately 10 patients with a diagnosis of PD without cognitive changes will be recruited to participate in this study. Patients will be eligible to participate if they have a diagnosis of PD of more than 2 years duration and have no significant cognitive changes.

Start Date01 Nov 2006

Sponsor / Collaborator

Institute for Neurodegenerative Disorders

[+1]

NCT00039702 / CompletedNot ApplicableIIT

SPECT Imaging of Alpha4beta2 Nicotinic Acetylcholine Receptors Using [123I]5-I-A-85380 in Alzheimer's Disease

The purpose of this study is to use brain imaging technology to examine the role of certain brain chemicals in individuals with Alzheimer's disease (AD) and in healthy volunteers.
Cognitive dysfunction in people with AD is thought to arise from decreased chemical activity in specific parts of the brain. Decreases in alpha4beta2 nicotinic acetycholine receptors (nAChRs) have been found in the brains of people who died with AD; however, the status of this receptor system in living brains remains unclear. This study will use single photon emission computed tomography (SPECT) to study this receptor system in people with AD who have mild to moderate dementia and in healthy volunteers. In addition, this study will examine the relationship between cognitive dysfunction and nAChR deficits in the brains of individuals with AD.
Participants with AD will have four clinic visits; healthy volunteers will have three visits. At Visit 1, participants will undergo a medical history, physical examination, and laboratory tests. Healthy volunteers will have a Mini-Mental State Examination (MMSE) cognitive function test. Participants with AD will have a MMSE and measurement of the severity of their dementia.
During Visit 2, participants will undergo a magnetic resonance imaging (MRI) scan of the brain.
At Visit 3, participants will undergo SPECT imaging.
Only participants with AD will participate in Visit 4. During this visit, cognitive testing will be performed.

Start Date01 Jun 2002

Sponsor / Collaborator

National Institute of Mental Health

100 Clinical Results associated with CHRNB2 x α4β2 receptor

100 Translational Medicine associated with CHRNB2 x α4β2 receptor

0 Patents (Medical) associated with CHRNB2 x α4β2 receptor

Literatures (Medical) associated with CHRNB2 x α4β2 receptor

01 Jul 2023·Nature geneticsQ1 · BIOLOGY

Rare coding variants in CHRNB2 reduce the likelihood of smoking.

Q1 · BIOLOGY

Article

Author: Jones, Marcus B ; Abecasis, Gonçalo R ; Gelfman, Sahar ; Cantor, Michael ; Baras, Aris ; Kapoor, Manav ; Ayer, Ariane ; Praveen, Kavita ; Avbersek, Andreja ; Chen, Esteban ; Chim, Shek Man ; Lederer, David ; Tapia-Conyer, Roberto ; Bao, Suying ; Stahl, Eli A ; Mbatchou, Joelle ; Collins, Rory ; Alegre, Jesus ; Anderson, Matthew ; Pavlopoulos, Elias ; Sharma, Deepika ; Jorgenson, Eric ; Marchini, Jonathan ; Sanchez, Robert ; Emberson, Jonathan ; Morales, Pablo Kuri ; Shuldiner, Alan R ; Watanabe, Kyoko ; Kessler, Michael D ; Kang, Hyun M ; Liedtke, Wolfgang ; Berumen, Jaime ; Balasubramanian, Suganthi ; Parikshak, Neelroop ; Coppola, Giovanni ; Otto, Jacqueline M ; Rajagopal, Veera M ; Quon, Peter ; Leblanc, Michelle ; Torres, Jason

Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2, encoding the β2 subunit of the α4β2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56-0.76, P = 1.9 × 10^-8). An independent common variant association in the protective direction ( rs2072659 ; OR = 0.96; CI = 0.94-0.98; P = 5.3 × 10^-6) was also evident, suggesting an allelic series. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine-mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.

01 Jun 2018·British Journal of PharmacologyQ2 · MEDICINE

Reduced α4 subunit expression in α4⁺⁻ and α4⁺⁻/β2⁺⁻ nicotinic acetylcholine receptors alters α4β2 subtype up‐regulation following chronic nicotine treatment

Q2 · MEDICINE

Article

Author: Gotti, Cecilia ; Fasoli, Francesca ; Moretti, Milena ; Marks, Michael J

Background and PurposeGenomic analysis has shown many variants in both CHRNA4 and CHRNB2, genes which encode the α4 and β2 subunits of nicotinic ACh receptors (nAChR) respectively. Some variants influence receptor expression, raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic exposure to nicotine increases expression of nAChRs, particularly α4β2‐nAChRs, in humans and laboratory animals. Here, we have evaluated whether the initial level of receptor expression affects the increase in expression.Experimental ApproachMice differing in expression of α4 and/or β2 nAChR subunits were chronically treated with saline, 0.25, 1.0 or 4.0 mg·kg−1·h−1nicotine. Brain preparations were analysed autoradiographically by [125I]‐epibatidine binding, immunoprecipitation and Western blotting.Key ResultsImmunochemical studies confirmed that most of the [3H]‐epibatidine binding corresponds to α4β2*‐nAChR and that increases in binding correspond to increases in α4 and β2 proteins. Consistent with previous reports, the dose‐dependent increase in nAChR in wild‐type mice following chronic nicotine treatment, measured with any of the methods, reached a maximum. Although receptor expression was reduced by approximately 50% in β2+− mice, the pattern of response to chronic treatment resembled that of wild‐type mice. In contrast, both α4+− and α4+−/β2+− exhibited relatively greater up‐regulation. Consistent with previous reports, α4β2α5‐nAChR did not increase in response to nicotine.Conclusions and ImplicationsThese results indicate that mice with reduced expression of the α4 nAChR subunit have a more robust response to chronic nicotine than mice with normal expression of this subunit.Linked ArticlesThis article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com.libproxy1.nus.edu.sg/doi/10.1111/bph.v175.11/issuetoc

01 Jun 2015·Progress in Neuro-Psychopharmacology and Biological PsychiatryQ2 · MEDICINE

The possible role of maternal bonding style and CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype

Q2 · MEDICINE

Article

Author: Lazary, Judit ; Dome, Peter ; Faludi, Gabor ; Dome, Balazs ; Csala, Iren ; Egervari, Luca

OBJECTIVESNeuronal nicotinic acetylcholinergic receptors (nAChR) and especially α4β2 nAChRs are the major targets for cessation medications and also for some promising antidepressant agents. Furthermore, depressive symptoms pose multifacet difficulties during cessation therapy. However, gene encoding for the β2 subunit of nAChRs has been poorly investigated in association with depression. Since both nicotine dependence (ND) and depressive phenotype are complex disorders, we investigated the effects of a significant early life experience, maternal bonding style (MB) and CHRNB2 gene SNPs on smoking-related depression.METHODSWe recruited two hundred and thirty-two treatment-seeking smokers in our study. Phenotypic variants were evaluated using the Fagerstrom Test for Nicotine Dependence (FTND), the Zung Self-Rating Depression Scale (ZSDS) and the Parental Bonding Instrument (PBI). Besides the total score (TS) of ZSDS, impulsivity (ZSDS-I) and suicidal ideation (ZSDS-S) were distinguished as phenotypic variable. DNAs were extracted from buccal mucosa samples and one SNP in promoter and two SNPs in 3' UTR of CHRNB2 gene were genotyped. GLM and ANOVA tests were performed for genotype associations and interaction analyses.RESULTSMaternal bonding had a significant impact on depressive phenotypes. Low care, high protection and affectionless control (ALC) were associated with ZSDS-TS and all subphenotypes of ZSDS. One SNP, the rs2072660 in 3' UTR, had a significant effect on the FTND score (p=0.010). Direct association of CHRNB2 variants and depressive phenotypes were not significant. However, in interaction with ALC, rs2072660 was significantly associated with ZSDS-S (p=0.005). MB had no significant effect on smoking-related phenotype.CONCLUSIONSOur results highlight the important role of 3' UTR in the CHRNB2 gene in the shared molecular background of ND and depressive phenotype. Parental bonding style can be suggested as a significant environmental factor in further GxE studies of depression. The presented significant GxE interaction on smoking-related suicidal subphenotype may help establish further investigations on development of more effective and safer smoking cessation and antidepressant agents.

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