title: 5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions.
abstract: 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 O2tension.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Guo
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D008807:Mice, Inbred BALB C; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D000255:Adenosine Triphosphate; D002118:Calcium