title: Selective serotonin reuptake inhibitors facilitate ANO6 (TMEM16F) current activation and phosphatidylserine exposure.
abstract: Anoctamin 6 (ANO6) is a member of the recently identified TMEM16/anoctamin protein family comprising Ca(2+)-activated Cl(-) channels that generate outward-rectifying ionic currents in response to intracellular Ca(2+) increase. ANO6 is also essential for Ca(2+)-dependent phospholipid scrambling required for blood coagulation. Selective serotonin reuptake inhibitors (SSRIs)--fluoxetine, sertraline, and paroxetine-that are used for the treatment of major depressive disorders can increase the risk of upper gastrointestinal bleeding after chronic treatment. However, at the earlier stage of intake, which is 1-7 days after the treatment, the possibility of blood coagulation might also increase, but transiently. Therefore, in this study, we investigated whether therapeutic SSRI concentrations affected the Cl(-) current or phospholipid scrambling activity of ANO6 by assessing ANO6 currents (I ANO6), phosphatidylserine (PS) exposure, and platelet aggregation. In the whole-cell patch mode, SSRIs facilitated Ca(2+)-dependent activation of IANO6 in ANO6-transfected cells, as evidenced by a significant decrease in the delay of IANO6 generation. On the other hand, in the inside-out patch clamp configuration, SSRIs showed an inhibitory effect on ANO6 currents, suggesting that SSRIs activate ANO6 via an indirect mechanism in intact cells. SSRIs also facilitated Ca(2+)-dependent PS exposure and α-thrombin-induced platelet aggregation. These results indicate that SSRIs at clinically relevant concentrations promote Ca(2+)-dependent activation of ANO6, which may have potential clinical implications such as the underlying mechanism of SSRI-induced adverse drug reactions.
authors: Department of Physiology, Dongguk University College of Medicine, 123 Dongdae-ro, Kyungju, 780-714, Republic of Korea.
authors: Hyun Jong
authors: HJ
authors: Kim
authors: Department of Pharmacology, BK21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors: Ikhyun
authors: I
authors: Jun
authors: Biochemistry and Molecular Biology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors: Jae Seok
authors: JS
authors: Yoon
authors: Department of Pharmacology, BK21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors: Jinsei
authors: J
authors: Jung
authors: Department of Physiology, Dongguk University College of Medicine, 123 Dongdae-ro, Kyungju, 780-714, Republic of Korea.
authors: Yung Kyu
authors: YK
authors: Kim
authors: Channelopathy Research Center (CRC), Dongguk University College of Medicine, 27 Dongguk-ro, Ilsan Dong-gu, Goyang, 410-773, Republic of Korea.|Department of Internal Medicine Graduate School of Medicine, Dongguk University, 27 Dongguk-ro, Ilsan Dong-gu, Goyang, 410-773, Republic of Korea.
authors: Woo Kyung
authors: WK
authors: Kim
authors: Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, 49 Busandaehak-ro, Yangsan, 626-870, Republic of Korea.
authors: Byung Joo
authors: BJ
authors: Kim
authors: Department of Laboratory Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seoul, 120-752, Republic of Korea.
authors: Jaewoo
authors: J
authors: Song
authors: Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongro-gu, Seoul, 110-799, Republic of Korea.
authors: Sung Joon
authors: SJ
authors: Kim
authors: Department of Physiology, Dongguk University College of Medicine, 123 Dongdae-ro, Kyungju, 780-714, Republic of Korea. jhnam@dongguk.ac.kr.|Channelopathy Research Center (CRC), Dongguk University College of Medicine, 27 Dongguk-ro, Ilsan Dong-gu, Goyang, 410-773, Republic of Korea. jhnam@dongguk.ac.kr.
authors: Joo Hyun
authors: JH
authors: Nam
authors: Department of Pharmacology, BK21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors: Min Goo
authors: MG
authors: Lee
mesh_terms: D000075368:Anoctamins; D001777:Blood Coagulation / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D018118:Chloride Channels / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018408:Patch-Clamp Techniques; D010718:Phosphatidylserines / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000187:drug effects / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D010974:Platelet Aggregation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D014162:Transfection
chemical_list: D000075368:Anoctamins; D018118:Chloride Channels; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; D034741:RNA, Small Interfering; D017367:Selective Serotonin Reuptake Inhibitors; D013917:Thrombin; C555078:ANO6 protein, human
keywords: Anoctamin 6; Calcium-activated Cl− channels; Selective serotonin reuptake inhibitors; TMEM16F
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