Identification of Sequence Motifs That Target Neuronal Nicotinic Receptors to Dendrites and Axons
Open accessAbstract
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a family of ligand-gated ion channels that play important roles in central and peripheral nervous systems. The subcellular distribution of neuronal nAChRs has important implications for function and is not well understood. Here, we analyzed the targeting of two major types of neuronal nAChRs by expressing epitope-tagged subunits in cultured hippocampal neurons. Surprisingly, the α7 nAChR (α7) and α4/β2 nAChR (α4β2) displayed distinct patterns of expression, with α7 targeted preferentially to the somatodendritic compartments, whereas α4β2 was localized to both axonal and dendritic domains. When fused to CD4 or IL2RA (interleukin 2 receptor α subunit) proteins, which are normally distributed ubiquitously, the M3–M4 intracellular loop from the α7 subunit promoted dendritic expression, whereas the homologous M3–M4 loop from the α4 subunit led to surface axonal expression. Systemic screening and alanine substitution further identified a 25-residue leucine motif ([DE]XXXL[LI]) containing an axonal targeting sequence within the α4 loop and a 48-residue dileucine and tyrosine motif (YXXØ) containing a dendritic targeting sequence from the α7 loop. These results provide valuable information in understanding diverse roles of neuronal nAChRs in mediating and modulating synaptic transmission, synaptic plasticity, and nicotine addiction.
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Exocytosis is required for upregulation, presumably because exocytosis is downstream from SePhaChARNS.
“Exocytosis is required for upregulation, presumably because exocytosis is downstream from SePhaChARNS (53).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [53]
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- Authors
- Xu, J., Zhu, Y., & Heinemann, S. F.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-09-20
- Volume
- 26
- Issue
- 38
- Pages
- 9780-9793
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674458
- OpenAlex
- W2032965800
- Cited by
- 96
- References
- 68
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 1 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 9 · 2012: 9
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (AG010435)
- National Institute on Aging (P01AG010435, AG010435)
- National Institute on Drug Abuse (DA018247, R01DA018247)
- National Institute of Neurological Disorders and Stroke (NS028709, R01NS028709)
- 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
- neuronal nicotinic acetylcholine receptors, alpha7 nAChR, alpha4beta2 nAChR, subcellular targeting, dendritic targeting, axon targeting, YXXΦ motif, dileucine motif, ligand-gated ion channels, hippocampal neurons, nicotine dependence
- MeSH terms
- Amino Acid Sequence, Animals, Axons, Cells, Cultured, Dendrites, Hippocampus, Humans, Molecular Sequence Data, Receptors, Nicotinic, Gene Targeting, Amino Acid Motifs, Rats
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