CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits
Homeostatic regulation of the partial pressure of CO2 (PCO2) is vital for life. Sensing of pH has been proposed as a sufficient proxy for determination of PCO2 and direct CO2-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivit...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2013-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/01213 |
| _version_ | 1811180652233490432 |
|---|---|
| author | Louise Meigh Sophie A Greenhalgh Thomas L Rodgers Martin J Cann David I Roper Nicholas Dale |
| author_facet | Louise Meigh Sophie A Greenhalgh Thomas L Rodgers Martin J Cann David I Roper Nicholas Dale |
| author_sort | Louise Meigh |
| collection | DOAJ |
| description | Homeostatic regulation of the partial pressure of CO2 (PCO2) is vital for life. Sensing of pH has been proposed as a sufficient proxy for determination of PCO2 and direct CO2-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivity, are directly modulated by CO2. A ‘carbamylation motif’, present in CO2-sensitive connexins (Cx26, Cx30, Cx32) but absent from a CO2-insensitive connexin (Cx31), comprises Lys125 and four further amino acids that orient Lys125 towards Arg104 of the adjacent subunit of the connexin hexamer. Introducing the carbamylation motif into Cx31 created a mutant hemichannel (mCx31) that was opened by increases in PCO2. Mutation of the carbamylation motif in Cx26 and mCx31 destroyed CO2 sensitivity. Course-grained computational modelling of Cx26 demonstrated that the proposed carbamate bridge between Lys125 and Arg104 biases the hemichannel to the open state. Carbamylation of Cx26 introduces a new transduction principle for physiological sensing of CO2. |
| first_indexed | 2024-04-11T09:05:43Z |
| format | Article |
| id | doaj.art-0fe28298656b46b2aa01234b17407a95 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:05:43Z |
| publishDate | 2013-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0fe28298656b46b2aa01234b17407a952022-12-22T04:32:37ZengeLife Sciences Publications LtdeLife2050-084X2013-11-01210.7554/eLife.01213CO2 directly modulates connexin 26 by formation of carbamate bridges between subunitsLouise Meigh0Sophie A Greenhalgh1Thomas L Rodgers2Martin J Cann3David I Roper4Nicholas Dale5School of Life Sciences, University of Warwick, Coventry, United KingdomSchool of Life Sciences, University of Warwick, Coventry, United KingdomBiophysical Sciences Institute, University of Durham, Durham, United Kingdom; Department of Chemistry, University of Durham, Durham, United KingdomDepartment of Chemistry, University of Durham, Durham, United Kingdom; School of Biological and Biomedical Sciences, University of Durham, Durham, United KingdomSchool of Life Sciences, University of Warwick, Coventry, United KingdomSchool of Life Sciences, University of Warwick, Coventry, United KingdomHomeostatic regulation of the partial pressure of CO2 (PCO2) is vital for life. Sensing of pH has been proposed as a sufficient proxy for determination of PCO2 and direct CO2-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivity, are directly modulated by CO2. A ‘carbamylation motif’, present in CO2-sensitive connexins (Cx26, Cx30, Cx32) but absent from a CO2-insensitive connexin (Cx31), comprises Lys125 and four further amino acids that orient Lys125 towards Arg104 of the adjacent subunit of the connexin hexamer. Introducing the carbamylation motif into Cx31 created a mutant hemichannel (mCx31) that was opened by increases in PCO2. Mutation of the carbamylation motif in Cx26 and mCx31 destroyed CO2 sensitivity. Course-grained computational modelling of Cx26 demonstrated that the proposed carbamate bridge between Lys125 and Arg104 biases the hemichannel to the open state. Carbamylation of Cx26 introduces a new transduction principle for physiological sensing of CO2.https://elifesciences.org/articles/01213respiratory chemosensitivityconnexinsignal transductionmembrane channel |
| spellingShingle | Louise Meigh Sophie A Greenhalgh Thomas L Rodgers Martin J Cann David I Roper Nicholas Dale CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits eLife respiratory chemosensitivity connexin signal transduction membrane channel |
| title | CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits |
| title_full | CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits |
| title_fullStr | CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits |
| title_full_unstemmed | CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits |
| title_short | CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits |
| title_sort | co2 directly modulates connexin 26 by formation of carbamate bridges between subunits |
| topic | respiratory chemosensitivity connexin signal transduction membrane channel |
| url | https://elifesciences.org/articles/01213 |
| work_keys_str_mv | AT louisemeigh co2directlymodulatesconnexin26byformationofcarbamatebridgesbetweensubunits AT sophieagreenhalgh co2directlymodulatesconnexin26byformationofcarbamatebridgesbetweensubunits AT thomaslrodgers co2directlymodulatesconnexin26byformationofcarbamatebridgesbetweensubunits AT martinjcann co2directlymodulatesconnexin26byformationofcarbamatebridgesbetweensubunits AT davidiroper co2directlymodulatesconnexin26byformationofcarbamatebridgesbetweensubunits AT nicholasdale co2directlymodulatesconnexin26byformationofcarbamatebridgesbetweensubunits |