Chatterjee, Susmita and Santos, Nathan and Holgate, Joan and Haass-Koffler, Carolina L. and Hopf, F. Woodward and Kharazia, Viktor and Lester, Henry and Bonci, Antonello and Bartlett, Selena E. (2013) The α5 Subunit Regulates the Expression and Function of α4*-Containing Neuronal Nicotinic Acetylcholine Receptors in the Ventral-Tegmental Area. PLoS ONE, 8 (7). Art. No. e68300. ISSN 1932-6203. PMCID PMC3712017. doi:10.1371/journal.pone.0068300. https://resolver.caltech.edu/CaltechAUTHORS:20130909-105437251
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Abstract
Human genetic association studies have shown gene variants in the α5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The α5 subunit is an accessory subunit that facilitates α4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the α4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of α5 in α4*-containing nAChRs in the VTA. We utilized transgenic mice α5+/+(α4YFP) and α5-/-(α4YFP) that allow the direct visualization and measurement of α4-YFP expression and the effect of the presence (α5+/+) and absence of α5 (-/-) subunit, as the antibodies for detecting the α4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the α5 subunit, the overall expression of α4 subunit is increased significantly by 60% in the VTA. Furthermore, the α5 subunit strengthens baseline nAChR currents, suggesting the increased expression of α4* nAChRs to be likely on the cell surface. While the presence of the α5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the α5 subunit in both the maintenance of α4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the α5α4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the α5 subunit is critical for controlling the expression and functional role of a population of α4*-containing nAChRs in the VTA.
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| Additional Information: | © 2013 Chatterjee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received February 24, 2012; Accepted June 2, 2013; Published July 15, 2013. Editor: Zhong-Ping Feng, University of Toronto, Canada. Funding: This work was supported by funding from the National Institutes of Health (NIH) 1RC2AA019429-01 (to SEB), NIH 1R01AA017924-01 (to SEB), NIH 1R01DA17279 (to HL), and the State of California for Medical Research on Alcohol and Substance Abuse through the University of California San Francisco (to SEB), and the California Tobacco-Related Disease Research Program (to HL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Stacy Taylor for excellent technical assistance in weaning and maintaining the breeding colony. We also thank San Francisco Nikon Imaging Center, at the University of California San Francisco for assistance with imaging. Author Contributions: Analyzed the data: JH CLHK SC. Wrote the manuscript: SC. Conceived the project: SEB AB. Design of the study and development of the manuscript: SC SEB. Performed electrophysiology experiments and analyzed data: SC. Performed biochemistry experiments: JH CLHK VK. Provided critical supplemental content and revisions: SC NS FWH VK SEB. Provided the α4-YFP mice: HL. Provided significant critiques to the manuscript: AB SEB FWH HL. Reviewed contents of the study and have approved final version for publications: SEB SC NS JH CLHK FWH VK HL AB. | ||||||||||||
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| Issue or Number: | 7 | ||||||||||||
| PubMed Central ID: | PMC3712017 | ||||||||||||
| DOI: | 10.1371/journal.pone.0068300 | ||||||||||||
| Record Number: | CaltechAUTHORS:20130909-105437251 | ||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20130909-105437251 | ||||||||||||
| Official Citation: | Chatterjee S, Santos N, Holgate J, Haass-Koffler CL, Hopf FW, et al. (2013) The α5 Subunit Regulates the Expression and Function of α4*- Containing Neuronal Nicotinic Acetylcholine Receptors in the Ventral-Tegmental Area. PLoS ONE 8(7): e68300. doi:10.1371/journal.pone.0068300 | ||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||
| ID Code: | 41170 | ||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||
| Deposited By: | Tony Diaz | ||||||||||||
| Deposited On: | 17 Sep 2013 20:35 | ||||||||||||
| Last Modified: | 10 Nov 2021 04:26 |
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