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Article

An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction

1
Department of Physiology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
2
Biomedical Information Engineering Lab, The University of Aizu, Aizu-Wakamatsu 965-8580, Japan
3
Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan
4
Department of Chemistry, Faculty of Science, Fukuoka University, Fukuoka 814-0180, Japan
*
Authors to whom correspondence should be addressed.
Academic Editors: Michael X. Zhu and Shuangtao Ma
Cells 2021, 10(5), 983; https://doi.org/10.3390/cells10050983
Received: 26 March 2021 / Revised: 16 April 2021 / Accepted: 21 April 2021 / Published: 22 April 2021
A Ca2+-activated monovalent cation-selective TRPM4 channel is abundantly expressed in the heart. Recently, a single gain-of-function mutation identified in the distal N-terminus of the human TRPM4 channel (Glu5 to Lys5; E7K) was found to be arrhythmogenic because of enhanced cell membrane expression. In this study, we conducted detailed analyses of this mutant channel from more functional aspects, in comparison with its wild type (WT). In an expression system, intracellular application of a short soluble PIP2 (diC8PIP2) restored the single-channel activities of both WT and E7K, which had quickly faded after membrane excision. The potency (Kd) of diC8PIP2 for this recovery was stronger in E7K than its WT (1.44 vs. 2.40 μM). FRET-based PIP2 measurements combined with the Danio rerio voltage-sensing phosphatase (DrVSP) and patch clamping revealed that lowering the endogenous PIP2 level by DrVSP activation reduced the TRPM4 channel activity. This effect was less prominent in E7K than its WT (apparent Kd values estimated from DrVSP-mediated PIP2 depletion: 0.97 and 1.06 μM, respectively), being associated with the differential PIP2-mediated modulation of voltage dependence. Moreover, intracellular perfusion of short N-terminal polypeptides containing either the ‘WT’ or ‘E7K’ sequences respectively attenuated the TRPM4 channel activation at whole-cell and single-channel levels, but in both configurations, the E7K polypeptide exerted greater inhibitory effects. These results collectively suggest that N-terminal interaction with endogenous PIP2 is essential for the TRPM4 channel to function, the extent of which may be abnormally strengthened by the E7K mutation through modulating voltage-dependent activation. The altered PIP2 interaction may account for the arrhythmogenic potential of this mutation. View Full-Text
Keywords: arrhythmogenicity; PIP2; TRP channel arrhythmogenicity; PIP2; TRP channel
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MDPI and ACS Style

Hu, Y.; Li, Q.; Kurahara, L.-H.; Shioi, N.; Hiraishi, K.; Fujita, T.; Zhu, X.; Inoue, R. An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction. Cells 2021, 10, 983. https://doi.org/10.3390/cells10050983

AMA Style

Hu Y, Li Q, Kurahara L-H, Shioi N, Hiraishi K, Fujita T, Zhu X, Inoue R. An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction. Cells. 2021; 10(5):983. https://doi.org/10.3390/cells10050983

Chicago/Turabian Style

Hu, Yaopeng, Qin Li, Lin-Hai Kurahara, Narumi Shioi, Keizo Hiraishi, Takayuki Fujita, Xin Zhu, and Ryuji Inoue. 2021. "An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction" Cells 10, no. 5: 983. https://doi.org/10.3390/cells10050983

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