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Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline.
Villatoro-Gómez, Kathya; Pacheco-Rojas, David O; Moreno-Galindo, Eloy G; Navarro-Polanco, Ricardo A; Tristani-Firouzi, Martin; Gazgalis, Dimitris; Cui, Meng; Sánchez-Chapula, José A; Ferrer, Tania.
Afiliação
  • Villatoro-Gómez K; Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col., Mexico.
  • Pacheco-Rojas DO; Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col., Mexico.
  • Moreno-Galindo EG; Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col., Mexico.
  • Navarro-Polanco RA; Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col., Mexico.
  • Tristani-Firouzi M; Nora Eccles Harrison CVRTI, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, UT 83113, USA.
  • Gazgalis D; Department of Pharmaceutical Sciences, Northeastern University School of Pharmacy, Boston, MA 02115, USA.
  • Cui M; Department of Pharmaceutical Sciences, Northeastern University School of Pharmacy, Boston, MA 02115, USA.
  • Sánchez-Chapula JA; Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col., Mexico.
  • Ferrer T; Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col., Mexico. Electronic address: tania@ucol.mx.
Biochem Pharmacol ; 152: 264-271, 2018 06.
Article em En | MEDLINE | ID: mdl-29621539
Amitriptyline (AMIT) is a compound widely prescribed for psychiatric and non-psychiatric conditions including depression, migraine, chronic pain, and anorexia. However, AMIT has been associated with risks of cardiac arrhythmia and sudden death since it can induce prolongation of the QT interval on the surface electrocardiogram and torsade de pointes ventricular arrhythmia. These complications have been attributed to the inhibition of the rapid delayed rectifier potassium current (IKr). The slow delayed rectifier potassium current (IKs) is the main repolarizing cardiac current when IKr is compromised and it has an important role in cardiac repolarization at fast heart rates induced by an elevated sympathetic tone. Therefore, we sought to characterize the effects of AMIT on Kv7.1/KCNE1 and homomeric Kv7.1 channels expressed in HEK-293H cells. Homomeric Kv7.1 and Kv7.1/KCNE1 channels were inhibited by AMIT in a concentration-dependent manner with IC50 values of 8.8 ±â€¯2.1 µM and 2.5 ±â€¯0.8 µM, respectively. This effect was voltage-independent for both homomeric Kv7.1 and Kv7.1/KCNE1 channels. Moreover, mutation of residues located on the P-loop and S6 domain along with molecular docking, suggest that T312, I337 and F340 are the most important molecular determinants for AMIT-Kv7.1 channel interaction. Our experimental findings and modeling suggest that AMIT preferentially blocks the open state of Kv7.1/KCNE1 channels by interacting with specific residues that were previously reported to be important for binding of other compounds, such as chromanol 293B and the benzodiazepine L7.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canais de Potássio de Abertura Dependente da Tensão da Membrana / Canal de Potássio KCNQ1 / Amitriptilina Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Biochem Pharmacol Ano de publicação: 2018 Tipo de documento: Article País de afiliação: México País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canais de Potássio de Abertura Dependente da Tensão da Membrana / Canal de Potássio KCNQ1 / Amitriptilina Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Biochem Pharmacol Ano de publicação: 2018 Tipo de documento: Article País de afiliação: México País de publicação: Reino Unido