Linked Life Data

19264848

Source:http://linkedlifedata.com/resource/pubmed/id/19264848

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2009-5-22
pubmed:abstractText
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.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
75
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1287-95
pubmed:dateRevised
2009-8-15
pubmed:meshHeading
pubmed-meshheading:19264848-Animals, pubmed-meshheading:19264848-Antidepressive Agents, pubmed-meshheading:19264848-Astrocytes, pubmed-meshheading:19264848-Binding Sites, pubmed-meshheading:19264848-Cell Line, pubmed-meshheading:19264848-Female, pubmed-meshheading:19264848-Fluoxetine, pubmed-meshheading:19264848-Humans, pubmed-meshheading:19264848-Hydrogen Bonding, pubmed-meshheading:19264848-Ligands, pubmed-meshheading:19264848-Models, Molecular, pubmed-meshheading:19264848-Mutagenesis, Site-Directed, pubmed-meshheading:19264848-Mutation, pubmed-meshheading:19264848-Nortriptyline, pubmed-meshheading:19264848-Oocytes, pubmed-meshheading:19264848-Patch-Clamp Techniques, pubmed-meshheading:19264848-Potassium Channels, Inwardly Rectifying, pubmed-meshheading:19264848-Protein Conformation, pubmed-meshheading:19264848-Quantitative Structure-Activity Relationship, pubmed-meshheading:19264848-Rats, pubmed-meshheading:19264848-Xenopus laevis
pubmed:year
2009
pubmed:articleTitle
Mutational and in silico analyses for antidepressant block of astroglial inward-rectifier Kir4.1 channel.
pubmed:affiliation
Department of Pharmacology, Center for Advanced Medical Engineering and Informatics, Osaka University, Japan.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't