Assembly of α4β2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons

Nashmi, Raad; Dickinson, Mary E.; McKinney, Sheri; Jareb, Mark; Labarca, Cesar; Fraser, Scott E.; Lester, Henry A.

doi:10.1523/jneurosci.23-37-11554.2003

Cited by 188Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

Assembly of α4β2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons

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Nashmi, Raad, Dickinson, Mary E., McKinney, Sheri, Jareb, Mark, Labarca, Cesar, Fraser, Scott E., Lester, Henry A.·2003·The Journal of Neuroscience

DOI 10.1523/jneurosci.23-37-11554.2003PMC PMC6740951

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Abstract

Fura-2 recording of Ca2+ influx was used to show that incubation in 1 microm nicotine (2-6 d) upregulates several pharmacological components of acetylcholine (ACh) responses in ventral midbrain cultures, including a MLA-resistant, DHbetaE-sensitive component that presumably corresponds to alpha4beta2 receptors. To study changes in alpha4beta2 receptor levels and assembly during this upregulation, we incorporated yellow and cyan fluorescent proteins (YFPs and CFPs) into the alpha4 or beta2 M3-M4 intracellular loops, and these subunits were coexpressed in human embryonic kidney (HEK) 293T cells and cultured ventral midbrain neurons. The fluorescent receptors resembled wild-type receptors in maximal responses to ACh, dose-response relations, ACh-induced Ca2+ influx, and somatic and dendritic distribution. Transfected midbrain neurons that were exposed to nicotine (1 d) displayed greater levels of fluorescent alpha4 and beta2 nicotinic ACh receptor (nAChR) subunits. As expected from the hetero-multimeric nature of alpha4beta2 receptors, coexpression of the alpha4-YFP and beta2-CFP subunits resulted in robust fluorescence resonance energy transfer (FRET), with a FRET efficiency of 22%. In midbrain neurons, dendritic alpha4beta2 nAChRs displayed greater FRET than receptors inside the soma, and in HEK293T cells, a similar increase was noted for receptors that were translocated to the surface during PKC stimulation. When cultured transfected midbrain neurons were incubated in 1 microm nicotine, there was increased FRET in the cell body, denoting increased assembly of alpha4beta2 receptors. Thus, changes in alpha4beta2 receptor assembly play a role in the regulation of alpha4beta2 levels and responses in both clonal cell lines and midbrain neurons, and the regulation may result from Ca2+-stimulated pathways.

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Higher β2*-nAChR availability in smokers may be due to increased assembly of α4 and β2 subunits in endoplasmic reticulum, increased transport of receptors to membrane, decreased receptor turnover, and/or presence of nicotine promoting intracellular maturation of α4β2-nAChR to high-affinity conformation.
“Higher β2*-nAChR availability in smokers may be due to a variety of molecular changes including increased assembly of α4 and β2 subunits in the endoplasmic reticulum9, increased transport of receptors to the membrane10, decreased receptor turnover11, and/or the presence of nicotine promoting intracellular maturation of the α4β2-nAChR to a high-affinity conformation12.”
From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [9]
Previous measurements have detected no differences between FP-labeled and unlabeled wt α4 subunits.
“We cannot state that the FP-labeled subunits perfectly emulate the unlabeled subunit, but our previous measurements have detected no differences between the FP-labeled and unlabeled wt α4 subunits.”
From Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning (2011) · cites this paper as Nashmi et al., 2003
α4β2 receptors exist in a mixed population whose nicotine EC50 values differ by 50- to 100-fold (~1 and ~100 μM).
“The α4β2 receptors exist in a mixed population whose nicotine EC50 values differ by 50- to 100-fold (70–73) (~1 and ~100 μM).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [73]

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“…it has also been suggested that the upregulation occurs as a consequence of increased assembly of 4 and 2 subunits in the endoplasmic reticulum (Nashmi et al., 2003), enhanced maturation and transport through the secretory path- way to the cell membrane (Sallette et al., 2005), increased…”
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Authors: Nashmi, R., Dickinson, M. E., McKinney, S., Jareb, M., Labarca, C., Fraser, S. E., & Lester, H. A.
Affiliations: California Institute of Technology (US)
ORCID: Nashmi, Raad
Fraser, Scott E.
Lester, Henry A.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2003-12-17
Volume: 23
Issue: 37
Pages: 11554-11567
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.23-37-11554.2003
PMC: PMC6740951
OpenAlex: W1776988577
Cited by: 188
References: 78
Citations by year: 2026: 1 · 2025: 3 · 2024: 6 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 10 · 2014: 14 · 2013: 11 · 2012: 11
FWCI: 4.14
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
Funders: Tobacco-Related Disease Research Program
National Institutes of Health (5p01hd037105-20, HD-37105)
National Institute of Neurological Disorders and Stroke (NS 11756, R01NS011756)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01-HD037105, HD37105)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: α4β2 nicotinic acetylcholine receptor, receptor assembly, fluorescence resonance energy transfer, midbrain neurons, calcium influx, receptor trafficking, PKC translocation, dendritic localization, acetylcholine response
MeSH terms: Animals, Cells, Cultured, Clone Cells, Dendrites, Humans, Mesencephalon, Microscopy, Fluorescence, Neurons, Nicotine, Receptors, Nicotinic, Up-Regulation, Chloride Channels, Patch-Clamp Techniques, Protein Subunits, Protein Transport, Fluorescence Resonance Energy Transfer, Mice

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Assembly of α4β2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons

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