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Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors

Limapichat, Walrati and Dougherty, Dennis A. and Lester, Henry A. (2014) Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors. Molecular Pharmacology, 86 (3). pp. 263-274. ISSN 0026-895X. PMCID PMC4152909. doi:10.1124/mol.114.093179. https://resolver.caltech.edu/CaltechAUTHORS:20141016-090934738

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Abstract

P2X receptors and nicotinic acetylcholine receptors (nAChRs) display functional and physical interactions in many cell types and heterologous expression systems, but interactions between α6β4-containing (α6β4*) nAChRs and P2X2 receptors and/or P2X3 receptors have not been fully characterized. We measured several types of crosstalk in oocytes coexpressing α6β4 nAChRs and P2X2, P2X3, or P2X2/3 receptors. A novel form of crosstalk occurs between α6β4 nAChRs and P2X2 receptors. P2X2 receptors were forced into a prolonged desensitized state upon activation by ATP through a mechanism that does not depend on the intracellular C terminus of the P2X2 receptors. Coexpression of α6β4 nAChRs with P2X3 receptors shifts the ATP dose-response relation to the right, even in the absence of acetylcholine (ACh). Moreover, currents become nonadditive when ACh and ATP are coapplied, as previously reported for other Cys-loop receptors interacting with P2X receptors, and this crosstalk is dependent on the presence of the P2X3 C-terminal domain. P2X2 receptors also functionally interact with α6β4β3 but through a different mechanism from α6β4. The interaction with P2X3 receptors is less pronounced for the α6β4β3 nAChR than the α6β4 nAChR. We also measured a functional interaction between the α6β4 nAChRs and the heteromeric P2X2/3 receptor. Experiments with the nAChR channel blocker mecamylamine on P2X2–α6β4 oocytes point to the loss of P2X2 channel activity during the crosstalk, whereas the ion channel pores of the P2X receptors were fully functional and unaltered by the receptor interaction for P2X2–α6β4β3, P2X2/3–α6β4, and P2X2/3–α6β4β3. These results may be relevant to dorsal root ganglion cells and to other neurons that coexpress these receptor subunits.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1124/mol.114.093179 DOIArticle
http://molpharm.aspetjournals.org/content/86/3/263PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152909/PubMed CentralArticle
ORCID:
AuthorORCID
Dougherty, Dennis A.0000-0003-1464-2461
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2014 by The American Society for Pharmacology and Experimental Therapeutics. Received April 11, 2014; accepted June 24, 2014. The authors thank J. Mogil, J. Wieskopf, R. Drenan, M. AlQazzaz, and C. I. Richards for discussion.
Issue or Number:3
PubMed Central ID:PMC4152909
DOI:10.1124/mol.114.093179
Record Number:CaltechAUTHORS:20141016-090934738
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141016-090934738
Official Citation:Limapichat, W., Dougherty, D. A., & Lester, H. A. (2014). Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors. Molecular Pharmacology, 86(3), 263-274. doi: 10.1124/mol.114.093179
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:50432
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:20 Oct 2014 19:06
Last Modified:10 Nov 2021 18:55

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