Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors
The β3 subunit of nicotinic acetylcholine receptors (nAChRs) participates in heteropentameric assemblies with some α and other β neuronal subunits forming a plethora of various subtypes, differing in their electrophysiological and pharmacological properties. While β3 has for several years been consi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/14/4642 |
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| author | Petros Giastas Athanasios Papakyriakou George Tsafaras Socrates J. Tzartos Marios Zouridakis |
| author_facet | Petros Giastas Athanasios Papakyriakou George Tsafaras Socrates J. Tzartos Marios Zouridakis |
| author_sort | Petros Giastas |
| collection | DOAJ |
| description | The β3 subunit of nicotinic acetylcholine receptors (nAChRs) participates in heteropentameric assemblies with some α and other β neuronal subunits forming a plethora of various subtypes, differing in their electrophysiological and pharmacological properties. While β3 has for several years been considered an accessory subunit without direct participation in the formation of functional binding sites, recent electrophysiology data have disputed this notion and indicated the presence of a functional (+) side on the extracellular domain (ECD) of β3. In this study, we present the 2.4 Å resolution crystal structure of the monomeric β3 ECD, which revealed rather distinctive loop C features as compared to those of α nAChR subunits, leading to intramolecular stereochemical hindrance of the binding site cavity. Vigorous molecular dynamics simulations in the context of full length pentameric β3-containing nAChRs, while not excluding the possibility of a β3 (+) binding site, demonstrate that this site cannot efficiently accommodate the agonist nicotine. From the structural perspective, our results endorse the accessory rather than functional role of the β3 nAChR subunit, in accordance with earlier functional studies on β3-containing nAChRs. |
| first_indexed | 2024-03-09T06:07:22Z |
| format | Article |
| id | doaj.art-86ba670c9d164cdfaefeea9be2c1d24a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T06:07:22Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-86ba670c9d164cdfaefeea9be2c1d24a2023-12-03T12:02:35ZengMDPI AGMolecules1420-30492022-07-012714464210.3390/molecules27144642Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic ReceptorsPetros Giastas0Athanasios Papakyriakou1George Tsafaras2Socrates J. Tzartos3Marios Zouridakis4Department of Neurobiology, Hellenic Pasteur Institute, GR11521 Athens, GreeceInstitute of Biosciences and Applications, NCSR “Demokritos”, GR15310 Athens, GreeceDepartment of Neurobiology, Hellenic Pasteur Institute, GR11521 Athens, GreeceDepartment of Neurobiology, Hellenic Pasteur Institute, GR11521 Athens, GreeceDepartment of Neurobiology, Hellenic Pasteur Institute, GR11521 Athens, GreeceThe β3 subunit of nicotinic acetylcholine receptors (nAChRs) participates in heteropentameric assemblies with some α and other β neuronal subunits forming a plethora of various subtypes, differing in their electrophysiological and pharmacological properties. While β3 has for several years been considered an accessory subunit without direct participation in the formation of functional binding sites, recent electrophysiology data have disputed this notion and indicated the presence of a functional (+) side on the extracellular domain (ECD) of β3. In this study, we present the 2.4 Å resolution crystal structure of the monomeric β3 ECD, which revealed rather distinctive loop C features as compared to those of α nAChR subunits, leading to intramolecular stereochemical hindrance of the binding site cavity. Vigorous molecular dynamics simulations in the context of full length pentameric β3-containing nAChRs, while not excluding the possibility of a β3 (+) binding site, demonstrate that this site cannot efficiently accommodate the agonist nicotine. From the structural perspective, our results endorse the accessory rather than functional role of the β3 nAChR subunit, in accordance with earlier functional studies on β3-containing nAChRs.https://www.mdpi.com/1420-3049/27/14/4642nAChRpentameric ligand gated ion channelspentamersprincipal binding sitecomplementary binding siteα4β2 nAChR |
| spellingShingle | Petros Giastas Athanasios Papakyriakou George Tsafaras Socrates J. Tzartos Marios Zouridakis Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors Molecules nAChR pentameric ligand gated ion channels pentamers principal binding site complementary binding site α4β2 nAChR |
| title | Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors |
| title_full | Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors |
| title_fullStr | Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors |
| title_full_unstemmed | Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors |
| title_short | Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors |
| title_sort | structural insights into the role of β3 nachr subunit in the activation of nicotinic receptors |
| topic | nAChR pentameric ligand gated ion channels pentamers principal binding site complementary binding site α4β2 nAChR |
| url | https://www.mdpi.com/1420-3049/27/14/4642 |
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