Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state
The subunits of the muscle-type nicotinic acetylcholine receptor (AChR) are not uniformly oriented in the resting closed conformation: the two α subunits are rotated relative to its non-α subunits. In contrast, all the subunits overlay well with one another when agonist is bound to the AChR, suggest...
| Main Authors: | , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier B.V.
2015
|
| Online Access: | http://hdl.handle.net/1721.1/96140 |
| _version_ | 1826202083782557696 |
|---|---|
| author | Tantama, Mathew Licht, Stuart |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Tantama, Mathew Licht, Stuart |
| author_sort | Tantama, Mathew |
| collection | MIT |
| description | The subunits of the muscle-type nicotinic acetylcholine receptor (AChR) are not uniformly oriented in the resting closed conformation: the two α subunits are rotated relative to its non-α subunits. In contrast, all the subunits overlay well with one another when agonist is bound to the AChR, suggesting that they are uniformly oriented in the open receptor. This gating-dependent increase in orientational uniformity due to rotation of the α subunits might affect the relative affinities of the two transmitter binding sites, making the two affinities dissimilar (functionally non-equivalent) in the initial ligand-bound closed state but similar (functionally equivalent) in the open state. To test this hypothesis, we measured single-channel activity of the αG153S gain-of-function mutant receptor evoked by choline, and estimated the resting closed-state and open-state affinities of the two transmitter binding sites. Both model-independent analyses and maximum-likelihood estimation of microscopic rate constants indicate that channel opening makes the binding sites' affinities more similar to each other. These results support the hypothesis that open-state affinities to the transmitter binding sites are primarily determined by the α subunits. |
| first_indexed | 2024-09-23T12:01:37Z |
| format | Article |
| id | mit-1721.1/96140 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:01:37Z |
| publishDate | 2015 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/961402022-09-27T23:35:33Z Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state Tantama, Mathew Licht, Stuart Massachusetts Institute of Technology. Department of Chemistry Tantama, Mathew Licht, Stuart The subunits of the muscle-type nicotinic acetylcholine receptor (AChR) are not uniformly oriented in the resting closed conformation: the two α subunits are rotated relative to its non-α subunits. In contrast, all the subunits overlay well with one another when agonist is bound to the AChR, suggesting that they are uniformly oriented in the open receptor. This gating-dependent increase in orientational uniformity due to rotation of the α subunits might affect the relative affinities of the two transmitter binding sites, making the two affinities dissimilar (functionally non-equivalent) in the initial ligand-bound closed state but similar (functionally equivalent) in the open state. To test this hypothesis, we measured single-channel activity of the αG153S gain-of-function mutant receptor evoked by choline, and estimated the resting closed-state and open-state affinities of the two transmitter binding sites. Both model-independent analyses and maximum-likelihood estimation of microscopic rate constants indicate that channel opening makes the binding sites' affinities more similar to each other. These results support the hypothesis that open-state affinities to the transmitter binding sites are primarily determined by the α subunits. 2015-03-20T18:49:54Z 2015-03-20T18:49:54Z 2009-05 2008-12 Article http://purl.org/eprint/type/JournalArticle 00052736 http://hdl.handle.net/1721.1/96140 Tantama, Mathew, and Stuart Licht. “Functional Equivalence of the Nicotinic Acetylcholine Receptor Transmitter Binding Sites in the Open State.” Biochimica et Biophysica Acta (BBA) - Biomembranes 1788, no. 5 (May 2009): 936–944. © 2009 Elsevier B.V. en_US http://dx.doi.org/10.1016/j.bbamem.2009.01.009 Biochimica et Biophysica Acta (BBA) - Biomembranes Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier B.V. Elsevier |
| spellingShingle | Tantama, Mathew Licht, Stuart Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| title | Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| title_full | Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| title_fullStr | Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| title_full_unstemmed | Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| title_short | Functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| title_sort | functional equivalence of the nicotinic acetylcholine receptor transmitter binding sites in the open state |
| url | http://hdl.handle.net/1721.1/96140 |
| work_keys_str_mv | AT tantamamathew functionalequivalenceofthenicotinicacetylcholinereceptortransmitterbindingsitesintheopenstate AT lichtstuart functionalequivalenceofthenicotinicacetylcholinereceptortransmitterbindingsitesintheopenstate |