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Selective serotonin reuptake inhibitors facilitate ANO6 (TMEM16F) current activation and phosphatidylserine exposure

 Hyun Jong Kim  ;  Ikhyun Jun  ;  Jae Seok Yoon  ;  Jinsei Jung  ;  Yung Kyu Kim  ;  Woo Kyung Kim  ;  Byung Joo Kim  ;  Jaewoo Song  ;  Sung Joon Kim  ;  Joo Hyun Nam  ;  Min Goo Lee 
 Pflugers Archiv - European Journal of Physiology, Vol.467(11) : 2243-2256, 2015 
Journal Title
 Pflugers Archiv - European Journal of Physiology 
Issue Date
Anoctamins ; Blood Coagulation/drug effects ; Calcium Signaling/drug effects ; Cell Line ; Chloride Channels/metabolism ; HEK293 Cells ; Humans ; Patch-Clamp Techniques ; Phosphatidylserines/metabolism* ; Phospholipid Transfer ; Proteins/drug effects ; Phospholipid Transfer Proteins/metabolism* ; Plasmids/genetics ; Platelet Aggregation/drug effects ; RNA, Small Interfering/pharmacology ; Serotonin Uptake Inhibitors/pharmacology* ; Thrombin/pharmacology ; Transfection
Anoctamin 6 ; Calcium-activated Cl− channels ; Selective serotonin reuptake inhibitors ; TMEM16F
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.
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1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Song, Jae Woo(송재우) ORCID logo https://orcid.org/0000-0002-1877-5731
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jun, Ik Hyun(전익현) ORCID logo https://orcid.org/0000-0002-2160-1679
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
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