Selective deletion of the α5 subunit differentially affects somatic–dendritic versus axonally targeted nicotinic ACh receptors in mouse
Abstract
We have compared the functional properties of nicotinic acetylcholine receptors (nAChRs) within both somatic and presynaptic domains of superior cervical ganglion (SCG) neurones from wild‐type (WT) mice with those expressed by SCG neurones from mice with a targeted deletion of the gene for the α5‐subunit. The functional profile of somatic nAChRs was assayed by direct macroscopic current recording and from measurements of nicotinic agonist‐induced calcium transients with fura‐2 imaging. The profile of nAChRs at presynaptic sites was assayed by measurement of nicotinic agonist‐induced transmitter release (as preloaded [3 H]noradrenaline) under conditions of action potential blockade. We have examined the responses to the nicotinic agonists acetylcholine, nicotine, cytisine, dimethylphenylpiperazinium iodide (DMPP) and epibatidine. Macroscopic current and calcium imaging assays revealed several differences in the functional profile of somatic nAChRs in WT SCG neurones compared with those from mice with the α5 subunit deleted. Somatic nAChRs in control animals were more potently activated by cytisine as compared to DMPP. In contrast, DMPP was consistently more potent than cytisine in mice lacking the α5 nAChR subunit. Differences in the somatic nAChR rank order of potency were most prominent after a least 1 day in vitro. The magnitude of somatic nAChR responses to nicotinic agonists was not substantially different in control mice compared with those of α5 subunit‐deleted animals. Comparison of presynaptic nAChR‐mediated responses in WT versus α5 subunit‐deleted animals revealed a very different set of changes in the functional profile of prejunctional nAChRs compared with somatic nAChRs. In contrast to somatic nAChRs, the responses of prejunctional receptors were markedly enhanced in α5 knockout animals compared with control. Furthermore, all prejunctional receptor responses were most potently activated by DMPP in both control and in α5 subunit‐deleted mice. Hence, the presence or absence of the α5 subunit did not affect the rank order of potency of agonists at preterminal sites but greatly affected the magnitude of presynaptic nAChR‐mediated responses. The enhanced efficacy of nicotine at presynaptic receptors was corroborated in an acute atrium preparation from postnatal α5 subunit‐deleted mice. These results confirm and significantly extend our previous observation that in the sympathetic nervous system, somatic and prejunctional receptors are different and rely on the presence of the α5 subunit in a distinct manner.
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Other studies on α5 knockout mice show changes in both presynaptic and somatodendritic nAChR responses.
“Other studies on α5 knockout mice show changes in both presynaptic and somatodendritic nAChR responses (111).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [111]
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- Authors
- Fischer, H., Orr‐Urtreger, A., Role, L. W., & Huck, S.
- Affiliations
- Medical University of Vienna (AT)
- Tel Aviv University (IL)
- Columbia University (US)
- Corresponding author
- Huck, Sigismund
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2005-02
- Volume
- 563
- Issue
- 1
- Pages
- 119-137
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- OpenAlex
- W1961626644
- Cited by
- 33
- References
- 50
- Citations by year
- 2025: 1 · 2024: 1 · 2020: 2 · 2019: 1 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 2
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS029071, NS22061, R01NS022061)
- 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 › Ion channel regulation and function
- Keywords
- nicotinic acetylcholine receptors, gene knockout, superior cervical ganglion, presynaptic nicotinic receptors, cytisine, DMPP, nicotine, epibatidine, calcium transients, noradrenaline release, sympathetic neurons, mouse model, postnatal development
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Ganglia, Sympathetic, Synaptic Transmission, Neurons, Receptors, Nicotinic, Structure-Activity Relationship, Sympathetic Nervous System, Gene Deletion, Receptors, Presynaptic, Nicotinic Antagonists, Calcium Signaling, Protein Subunits, Mice
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