Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block
In the heart, TRPM4 is most abundantly distributed in the conduction system. Previously, a single mutation, ‘E7K’, was identified in its distal N-terminus to cause conduction disorder because of enhanced cell-surface expression. It remains, however, unclear how this expression increase leads to cond...
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/8513 |
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| author | Yaopeng Hu Qin Li Yanghua Shen Takayuki Fujita Xin Zhu Ryuji Inoue |
| author_facet | Yaopeng Hu Qin Li Yanghua Shen Takayuki Fujita Xin Zhu Ryuji Inoue |
| author_sort | Yaopeng Hu |
| collection | DOAJ |
| description | In the heart, TRPM4 is most abundantly distributed in the conduction system. Previously, a single mutation, ‘E7K’, was identified in its distal N-terminus to cause conduction disorder because of enhanced cell-surface expression. It remains, however, unclear how this expression increase leads to conduction failure rather than abnormally enhanced cardiac excitability. To address this issue theoretically, we mathematically formulated the gating kinetics of the E7K-mutant TRPM4 channel by a combined use of voltage jump analysis and ionomycin-perforated cell-attached recording technique and incorporated the resultant rate constants of opening and closing into a human Purkinje fiber single-cell action potential (AP) model (Trovato model) to perform 1D-cable simulations. The results from TRPM4 expressing HEK293 cells showed that as compared with the wild-type, the open state is much preferred in the E7K mutant with increased voltage-and Ca<sup>2+</sup>-sensitivities. These theoretical predictions were confirmed by power spectrum and single channel analyses of expressed wild-type and E7K-mutant TRPM4 channels. In our modified Trovato model, the facilitated opening of the E7K mutant channel markedly prolonged AP duration with concomitant depolarizing shifts of the resting membrane potential in a manner dependent on the channel density (or maximal activity). This was, however, little evident in the wild-type TRPM4 channel. Moreover, 1D-cable simulations with the modified Trovato model revealed that increasing the density of E7K (but not of wild-type) TRPM4 channels progressively reduced AP conduction velocity eventually culminating in complete conduction block. These results clearly suggest the brady-arrhythmogenicity of the E7K mutant channel which likely results from its pathologically enhanced activity. |
| first_indexed | 2024-03-10T08:45:57Z |
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| language | English |
| last_indexed | 2024-03-10T08:45:57Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7d96f5d2ef944177862820167a3b35952023-11-22T07:56:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216851310.3390/ijms22168513Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction BlockYaopeng Hu0Qin Li1Yanghua Shen2Takayuki Fujita3Xin Zhu4Ryuji Inoue5Department of Physiology, Fukuoka University School of Medicine, Fukuoka 814-0180, JapanBiomedical Information Engineering Lab, Division of Information Systems, the University of Aizu, Aizu-Wakamatsu 965-8580, JapanBiomedical Information Engineering Lab, Division of Information Systems, the University of Aizu, Aizu-Wakamatsu 965-8580, JapanDepartment of Physiology, Fukuoka University School of Medicine, Fukuoka 814-0180, JapanBiomedical Information Engineering Lab, Division of Information Systems, the University of Aizu, Aizu-Wakamatsu 965-8580, JapanDepartment of Physiology, Fukuoka University School of Medicine, Fukuoka 814-0180, JapanIn the heart, TRPM4 is most abundantly distributed in the conduction system. Previously, a single mutation, ‘E7K’, was identified in its distal N-terminus to cause conduction disorder because of enhanced cell-surface expression. It remains, however, unclear how this expression increase leads to conduction failure rather than abnormally enhanced cardiac excitability. To address this issue theoretically, we mathematically formulated the gating kinetics of the E7K-mutant TRPM4 channel by a combined use of voltage jump analysis and ionomycin-perforated cell-attached recording technique and incorporated the resultant rate constants of opening and closing into a human Purkinje fiber single-cell action potential (AP) model (Trovato model) to perform 1D-cable simulations. The results from TRPM4 expressing HEK293 cells showed that as compared with the wild-type, the open state is much preferred in the E7K mutant with increased voltage-and Ca<sup>2+</sup>-sensitivities. These theoretical predictions were confirmed by power spectrum and single channel analyses of expressed wild-type and E7K-mutant TRPM4 channels. In our modified Trovato model, the facilitated opening of the E7K mutant channel markedly prolonged AP duration with concomitant depolarizing shifts of the resting membrane potential in a manner dependent on the channel density (or maximal activity). This was, however, little evident in the wild-type TRPM4 channel. Moreover, 1D-cable simulations with the modified Trovato model revealed that increasing the density of E7K (but not of wild-type) TRPM4 channels progressively reduced AP conduction velocity eventually culminating in complete conduction block. These results clearly suggest the brady-arrhythmogenicity of the E7K mutant channel which likely results from its pathologically enhanced activity.https://www.mdpi.com/1422-0067/22/16/8513transient receptor potential melastatin subfamilyinherent cardiac arrhythmiaconduction blockgating analysisnumerical simulation |
| spellingShingle | Yaopeng Hu Qin Li Yanghua Shen Takayuki Fujita Xin Zhu Ryuji Inoue Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block International Journal of Molecular Sciences transient receptor potential melastatin subfamily inherent cardiac arrhythmia conduction block gating analysis numerical simulation |
| title | Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block |
| title_full | Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block |
| title_fullStr | Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block |
| title_full_unstemmed | Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block |
| title_short | Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block |
| title_sort | theoretical investigation of the mechanism by which a gain of function mutation of the trpm4 channel causes conduction block |
| topic | transient receptor potential melastatin subfamily inherent cardiac arrhythmia conduction block gating analysis numerical simulation |
| url | https://www.mdpi.com/1422-0067/22/16/8513 |
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