دورية أكاديمية
أعرض في EDS

High-potency block of Kir4.1 channels by pentamidine: Molecular basis.

التفاصيل البيبلوغرافية
العنوان: High-potency block of Kir4.1 channels by pentamidine: Molecular basis.
المؤلفون: Aréchiga-Figueroa IA; CONACYT, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, SLP, Mexico., Marmolejo-Murillo LG; Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, Col, Mexico., Cui M; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA., Delgado-Ramírez M; Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, SLP, Mexico., van der Heyden MAG; Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands., Sánchez-Chapula JA; Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, Col, Mexico., Rodríguez-Menchaca AA; Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, SLP, Mexico. Electronic address: aldo.rodriguez@uaslp.mx.
المصدر: European journal of pharmacology [Eur J Pharmacol] 2017 Nov 15; Vol. 815, pp. 56-63. Date of Electronic Publication: 2017 Oct 06.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.
مواضيع طبية MeSH: Pentamidine/*pharmacology , Potassium Channel Blockers/*pharmacology , Potassium Channels, Inwardly Rectifying/*antagonists & inhibitors, Binding Sites ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Molecular Docking Simulation ; Pentamidine/metabolism ; Potassium Channel Blockers/chemistry ; Potassium Channel Blockers/metabolism ; Protein Conformation
مستخلص: Inward rectifier potassium (Kir) channels are expressed in almost all mammalian tissues and contribute to a wide range of physiological processes. Kir4.1 channel expression is found in the brain, inner ear, eye, and kidney. Loss-of-function mutations in the pore-forming Kir4.1 subunit cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (SeSAME/EST syndrome). Despite its importance in physiological and pathological conditions, pharmacological research of Kir4.1 is limited. Here, we characterized the effect of pentamidine on Kir4.1 channels using electrophysiology, mutagenesis and computational methods. Pentamidine potently inhibited Kir4.1 channels when applied to the cytoplasmic side under inside-out patch clamp configuration (IC 50 = 97nM). The block was voltage dependent. Molecular modeling predicted the binding of pentamidine to the transmembrane pore region of Kir4.1 at aminoacids T127, T128 and E158. Mutation of each of these residues reduced the potency of pentamidine to block Kir4.1 channels. A pentamidine analog (PA-6) inhibited Kir4.1 with similar potency (IC 50 = 132nM). Overall, this study shows that pentamidine blocks Kir4.1 channels interacting with threonine and glutamate residues in the transmembrane pore region. These results can be useful to design novel compounds with major potency and specificity over Kir4.1 channels.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Kir4.1; Molecular modeling; Mutagenesis; PA-6; Pentamidine
المشرفين على المادة: 0 (Kcnj10 (channel))
0 (Potassium Channel Blockers)
0 (Potassium Channels, Inwardly Rectifying)
673LC5J4LQ (Pentamidine)
تواريخ الأحداث: Date Created: 20171011 Date Completed: 20180208 Latest Revision: 20180208
رمز التحديث: 20231215
DOI: 10.1016/j.ejphar.2017.10.009
PMID: 28993158
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0712
DOI:10.1016/j.ejphar.2017.10.009