Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors
In the nervous system, nicotinic acetylcholine receptors (nAChRs) rapidly transduce a chemical signal into one that is electrical via ligand-gated ion flux through the central channel of the receptor. However, some nAChR subunits are expressed by non-excitable cells where signal transduction apparen...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.981760/full |
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| author | Arik J. Hone Arik J. Hone J. Michael McIntosh J. Michael McIntosh J. Michael McIntosh |
| author_facet | Arik J. Hone Arik J. Hone J. Michael McIntosh J. Michael McIntosh J. Michael McIntosh |
| author_sort | Arik J. Hone |
| collection | DOAJ |
| description | In the nervous system, nicotinic acetylcholine receptors (nAChRs) rapidly transduce a chemical signal into one that is electrical via ligand-gated ion flux through the central channel of the receptor. However, some nAChR subunits are expressed by non-excitable cells where signal transduction apparently occurs through non-ionic mechanisms. One such nAChR subunit, α10, is present in a discreet subset of immune cells and has been implicated in pathologies including cancer, neuropathic pain, and chronic inflammation. Longstanding convention holds that human α10 subunits require co-assembly with α9 subunits for function. Here we assessed whether cholinergic ligands can enable or uncover ionic functions from homomeric α10 nAChRs. Xenopus laevis oocytes expressing human α10 subunits were exposed to a panel of ligands and examined for receptor activation using voltage-clamp electrophysiology. Functional expression of human α10 nAChRs was achieved by exposing the oocytes to the alkaloids strychnine, brucine, or methyllycaconitine. Furthermore, acute exposure to the alkaloid ligands significantly enhanced ionic responses. Acetylcholine-gated currents mediated by α10 nAChRs were potently inhibited by the snake toxins α-bungarotoxin and α-cobratoxin but not by α-conotoxins that target α9 and α9α10 nAChRs. Our findings indicate that human α10 homomers are expressed in oocytes and exposure to certain ligands can enable ionic functions. To our knowledge, this is the first demonstration that human α10 subunits can assemble as functional homomeric nAChRs. These findings have potential implications for receptor regulatory-mechanisms and will enable structural, functional, and further pharmacological characterization of human α10 nAChRs. |
| first_indexed | 2024-04-12T18:53:36Z |
| format | Article |
| id | doaj.art-13e4de7b005b4f66b4ce7b2e24b69f0e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T18:53:36Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-13e4de7b005b4f66b4ce7b2e24b69f0e2022-12-22T03:20:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.981760981760Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptorsArik J. Hone0Arik J. Hone1J. Michael McIntosh2J. Michael McIntosh3J. Michael McIntosh4School of Biological Sciences, University of Utah, Salt Lake City, UT, United StatesMIRECC, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, United StatesSchool of Biological Sciences, University of Utah, Salt Lake City, UT, United StatesDepartment of Psychiatry, University of Utah, Salt Lake City, UT, United StatesGeorge E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, United StatesIn the nervous system, nicotinic acetylcholine receptors (nAChRs) rapidly transduce a chemical signal into one that is electrical via ligand-gated ion flux through the central channel of the receptor. However, some nAChR subunits are expressed by non-excitable cells where signal transduction apparently occurs through non-ionic mechanisms. One such nAChR subunit, α10, is present in a discreet subset of immune cells and has been implicated in pathologies including cancer, neuropathic pain, and chronic inflammation. Longstanding convention holds that human α10 subunits require co-assembly with α9 subunits for function. Here we assessed whether cholinergic ligands can enable or uncover ionic functions from homomeric α10 nAChRs. Xenopus laevis oocytes expressing human α10 subunits were exposed to a panel of ligands and examined for receptor activation using voltage-clamp electrophysiology. Functional expression of human α10 nAChRs was achieved by exposing the oocytes to the alkaloids strychnine, brucine, or methyllycaconitine. Furthermore, acute exposure to the alkaloid ligands significantly enhanced ionic responses. Acetylcholine-gated currents mediated by α10 nAChRs were potently inhibited by the snake toxins α-bungarotoxin and α-cobratoxin but not by α-conotoxins that target α9 and α9α10 nAChRs. Our findings indicate that human α10 homomers are expressed in oocytes and exposure to certain ligands can enable ionic functions. To our knowledge, this is the first demonstration that human α10 subunits can assemble as functional homomeric nAChRs. These findings have potential implications for receptor regulatory-mechanisms and will enable structural, functional, and further pharmacological characterization of human α10 nAChRs.https://www.frontiersin.org/articles/10.3389/fphar.2022.981760/fullα10 nicotinic acetylcholine receptorsα-conotoxin RgIAstrychnous nux vomicaneuropathic painchronic inflammation |
| spellingShingle | Arik J. Hone Arik J. Hone J. Michael McIntosh J. Michael McIntosh J. Michael McIntosh Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors Frontiers in Pharmacology α10 nicotinic acetylcholine receptors α-conotoxin RgIA strychnous nux vomica neuropathic pain chronic inflammation |
| title | Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors |
| title_full | Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors |
| title_fullStr | Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors |
| title_full_unstemmed | Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors |
| title_short | Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors |
| title_sort | alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors |
| topic | α10 nicotinic acetylcholine receptors α-conotoxin RgIA strychnous nux vomica neuropathic pain chronic inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.981760/full |
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