Your browser doesn't support javascript.
loading
High-potency block of Kir4.1 channels by pentamidine: Molecular basis.
Aréchiga-Figueroa, Iván A; Marmolejo-Murillo, Leticia G; Cui, Meng; Delgado-Ramírez, Mayra; van der Heyden, Marcel A G; Sánchez-Chapula, José A; Rodríguez-Menchaca, Aldo A.
Afiliação
  • 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.
Eur J Pharmacol ; 815: 56-63, 2017 Nov 15.
Article em En | MEDLINE | ID: mdl-28993158
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 (IC50 = 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 (IC50 = 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.
Assuntos
Palavras-chave
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: Pentamidina / Canais de Potássio Corretores do Fluxo de Internalização / Bloqueadores dos Canais de Potássio Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2017 Tipo de documento: Article País de afiliação: México País de publicação: Holanda
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: Pentamidina / Canais de Potássio Corretores do Fluxo de Internalização / Bloqueadores dos Canais de Potássio Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2017 Tipo de documento: Article País de afiliação: México País de publicação: Holanda