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α4* Nicotinic Receptors in preBotzinger Complex Mediate Cholinergic/Nicotinic Modulation of Respiratory Rhythm

Shao, Xuesi M. and Tan, Wenbin and Xiu, Joanne and Puskar, Nyssa and Fonck, Carlos and Lester, Henry A. and Feldman, Jack L. (2008) α4* Nicotinic Receptors in preBotzinger Complex Mediate Cholinergic/Nicotinic Modulation of Respiratory Rhythm. Journal of Neuroscience, 28 (2). pp. 519-528. ISSN 0270-6474. PMCID PMC3477875. doi:10.1523/jneurosci.3666-07.2008.

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Acetylcholine and nicotine can modulate respiratory patterns by acting on nicotinic acetylcholine receptors (nAChRs) in the preBötzinger complex (preBötC). To further explore the molecular composition of these nAChRs, we studied a knock-in mouse strain with a leucine-to-alanine mutation in the M2 pore-lining region (L9′A) of the nAChR α4 subunit; this mutation renders α4-containing receptors hypersensitive to agonists. We recorded respiratory-related rhythmic motor activity from hypoglossal nerve (XIIn) and patch-clamped preBötC inspiratory neurons in an in vitro medullary slice preparation from neonatal mice. Nicotine affected respiratory rhythm at concentrations ∼100-fold lower in the homozygous L9′A knock-in mice compared with wild-type mice. Bath application of 5 nm nicotine increased the excitability of preBötC inspiratory neurons, increased respiratory frequency, and induced tonic/seizure-like activities in XIIn in L9′A mice, effects similar to those induced by 1 μm nicotine in wild-type mice. In L9′A mice, microinjection of low nanomolar concentrations of nicotine into the preBötC increased respiratory frequency, whereas injection into the ipsilateral hypoglossal (XII) nucleus induced tonic/seizure-like activity. The α4*-selective nAChR antagonist dihydro-β-erythroidine produced opposite effects and blocked the nicotinic responses. These data, showing that nAChRs in the preBötC and XII nucleus in L9'A mice are hypersensitive to nicotine and endogenous ACh, suggest that functional α4* nAChRs are present in the preBötC. They mediate cholinergic/nicotinic modulation of the excitability of preBötC inspiratory neurons and of respiratory rhythm. Furthermore, functional α4* nAChRs are present in XII nucleus and mediate cholinergic/nicotinic modulation of tonic activity in XIIn.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2008 Society for Neuroscience. Received May 11, 2007; revised Dec. 4, 2007; accepted Dec. 4, 2007. This work was supported by Tobacco-Related Disease Research Program (California) Grants 10RT-0241 and 12RT-0245, by National Institutes of Health Grants HL40959 and DA17279, and by Philip Morris USA/International.
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program10RT-0241
California Tobacco-Related Disease Research Program12RT-0245
Philip Morris USA/InternationalUNSPECIFIED
Subject Keywords:L9′A knock-in mice; α4 subunit; preBötzinger complex; inspiratory neurons; hypoglossal nucleus; nicotine
Issue or Number:2
PubMed Central ID:PMC3477875
Record Number:CaltechAUTHORS:20200421-112849285
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Official Citation:α4* Nicotinic Receptors in preBötzinger Complex Mediate Cholinergic/Nicotinic Modulation of Respiratory Rhythm. Xuesi M. Shao, Wenbin Tan, Joanne Xiu, Nyssa Puskar, Carlos Fonck, Henry A. Lester, Jack L. Feldman. Journal of Neuroscience 9 January 2008, 28 (2) 519-528; DOI: 10.1523/JNEUROSCI.3666-07.2008
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102698
Deposited By: Tony Diaz
Deposited On:21 Apr 2020 20:13
Last Modified:16 Nov 2021 18:14

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