5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions

Wang, Qingyi, Zhang, Huiyuan, Xu, Hao, Guo, Dongqing, Shi, Hui, Li, Yuan, Zhang, Weiwei and Gu, Yuchun (2016). 5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions. Scientific Reports, 6 ,


5-HT has been reported to possess significant effects on cardiac activities, but activation of 5-HTR on the cell membrane failed to illustrate the controversial cardiac reaction. Because 5-HT constantly comes across the cell membrane via 5-HT transporter (5-HTT) into the cytoplasm, whether 5-HTR is functional present on the cellular organelles is unknown. Here we show 5-HTR3 and 5-HTR4 were located in cardiac mitochondria, and regulated mitochondrial activities and cellular functions. Knock down 5-HTR3 and 5-HTR4 in neonatal cardiomyocytes resulted in significant increase of cell damage in response to hypoxia, and also led to alternation in heart beating. Activation of 5-HTR4 attenuated mitochondrial Ca2+ uptake under the both normoxic and hypoxic conditions, whereas 5-HTR3 augmented Ca2+ uptake only under hypoxia. 5-HTR3 and 5-HTR4 exerted the opposite effects on the mitochondrial respiration: 5-HTR3 increased RCR (respiration control ratio), but 5-HTR4 reduced RCR. Moreover, activation of 5-HTR3 and 5-HTR4 both significantly inhibited the opening of mPTP. Our results provided the first evidence that 5-HTR as a GPCR and an ion channel, functionally expressed in mitochondria and participated in the mitochondria function and regulation to maintain homeostasis of mitochondrial [Ca2+], ROS, and ATP generation efficiency in cardiomyocytes in response to stress and O2 tension.

Publication DOI: https://doi.org/10.1038/srep37336
Divisions: Aston Medical School
Additional Information: © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: research grants held by YCG (973 Project No. 2013CB531206, 973 Project No. 2012CB517803 and NSF No. 81170236, No. 31127001, No. 81570245 and No. 31221002).
Uncontrolled Keywords: Arrhythmias Energy metabolism
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Related URLs: http://www.natu ... icles/srep37336 (Publisher URL)
Published Date: 2016-11-22
Authors: Wang, Qingyi
Zhang, Huiyuan
Xu, Hao
Guo, Dongqing
Shi, Hui
Li, Yuan
Zhang, Weiwei
Gu, Yuchun



Version: Published Version

License: Creative Commons Attribution

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