Mutational and in silico analyses for antidepressant block of astroglial inward-rectifier Kir4.1 channel

Kazuharu Furutani, Yukihiro Ohno, Atsushi Inanobe, Hiroshi Hibino, Yoshihisa Kurachi

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Drug interaction with target proteins including ion channels is essential for pharmacological control of various cellular functions, but the majority of its molecular mechanisms is still elusive. We recently found that a series of antidepressants preferentially block astroglial K+-buffering inwardly rectifying potassium channel (Kir) 4.1 channels over Kir1.1 channels. Here, using electrophysiological analyses of drug action on mutated Kir4.1 channel as well as computational analyses of three-dimensional (3D) arrangements of the ligands (i.e., bidirectional analyses), we examined the underlying mechanism for the antidepressant-Kir4.1 channel interaction. First, the effects of the selective serotonin reuptake inhibitor fluoxetine and the tricyclic antidepressant nortriptyline on chimeric and site-directed mutants of Kir4.1 expressed in Xenopus laevis oocytes were examined using the two-electrode voltage-clamp technique. Two amino acids, Thr128 and Glu158, on transmembrane domain 2 were critical for the drug inhibition of the current. The closed and open conformation models of the Kir4.1 pore suggested that both residues faced the central cavity, and they were positioned within a geometrical range capable of interacting with the drugs. Second, to represent molecular properties of active ligands in geometric terms, a 3D quantitative structure-activity relationship model of antidepressants was generated, which suggested that they share common features bearing a hydrogen bond acceptor and a positively charged moiety. 3D structures and physicochemical features of receptor and ligand were fitted together. Our results strongly suggest that antidepressants interact with Kir4.1 channel pore residues by hydrogen bond and ionic interactions, which account for their preferential inhibitory action on Kir4.1 current. This study may represent a possible general approach for the understanding of the mechanism of ligand-protein interactions.

Original languageEnglish (US)
Pages (from-to)1287-1295
Number of pages9
JournalMolecular Pharmacology
Volume75
Issue number6
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Fingerprint

Computer Simulation
Antidepressive Agents
Ligands
Hydrogen
Pharmaceutical Preparations
Inwardly Rectifying Potassium Channel
Nortriptyline
Quantitative Structure-Activity Relationship
Tricyclic Antidepressive Agents
Fluoxetine
Xenopus laevis
Serotonin Uptake Inhibitors
Patch-Clamp Techniques
Drug Interactions
Ion Channels
Oocytes
Electrodes
Proteins
Pharmacology
Amino Acids

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Mutational and in silico analyses for antidepressant block of astroglial inward-rectifier Kir4.1 channel. / Furutani, Kazuharu; Ohno, Yukihiro; Inanobe, Atsushi; Hibino, Hiroshi; Kurachi, Yoshihisa.

In: Molecular Pharmacology, Vol. 75, No. 6, 01.06.2009, p. 1287-1295.

Research output: Contribution to journalArticle

Furutani, Kazuharu ; Ohno, Yukihiro ; Inanobe, Atsushi ; Hibino, Hiroshi ; Kurachi, Yoshihisa. / Mutational and in silico analyses for antidepressant block of astroglial inward-rectifier Kir4.1 channel. In: Molecular Pharmacology. 2009 ; Vol. 75, No. 6. pp. 1287-1295.
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