Linked Life Data

16311240

Source:http://linkedlifedata.com/resource/pubmed/id/16311240

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2006-1-23
pubmed:abstractText
The genetic disease cystic fibrosis (CF) is caused by loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two CF mutants, G551D and G1349D, affect equivalent residues in the highly conserved LSGGQ motifs that are essential components of the ATP-binding sites of CFTR. Both mutants severely disrupt CFTR channel gating by decreasing mean burst duration (MBD) and prolonging greatly the interburst interval (IBI). To identify small molecules that rescue the gating defects of G551D- and G1349D-CFTR and understand better how these agents work, we used the patch clamp technique to study the effects on G551D- and G1349D-CFTR of phloxine B, pyrophosphate (PP(i)), and 2'-deoxy ATP (2'-dATP), three agents that strongly enhance CFTR channel gating. Phloxine B (5 microm) potentiated robustly G551D-CFTR Cl- channels by altering both MBD and IBI. In contrast, phloxine B (5 microm) decreased the IBI of G1349D-CFTR, but this effect was insufficient to rescue G1349D-CFTR channel gating. PP(i) (5 mm) potentiated weakly G551D-CFTR and was without effect on the G1349D-CFTR Cl- channel. However, by altering both MBD and IBI, albeit with different efficacies, 2'-dATP (1 mm) potentiated both G551D- and G1349D-CFTR Cl- channels. Using the ATP-driven nucleotide-binding domain dimerization model of CFTR channel gating, we suggest that phloxine B, PP(i) and 2'-dATP alter channel gating by distinct mechanisms. We conclude that G551D- and G1349D-CFTR have distinct pharmacological profiles and speculate that drug therapy for CF is likely to be mutation-specific.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1970-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:16311240-Adenosine Triphosphate, pubmed-meshheading:16311240-Amino Acid Motifs, pubmed-meshheading:16311240-Animals, pubmed-meshheading:16311240-Binding Sites, pubmed-meshheading:16311240-Cell Line, Tumor, pubmed-meshheading:16311240-Chloride Channels, pubmed-meshheading:16311240-Cystic Fibrosis Transmembrane Conductance Regulator, pubmed-meshheading:16311240-Deoxyadenine Nucleotides, pubmed-meshheading:16311240-Dimerization, pubmed-meshheading:16311240-Diphosphates, pubmed-meshheading:16311240-Dose-Response Relationship, Drug, pubmed-meshheading:16311240-Electrophysiology, pubmed-meshheading:16311240-Eosine I Bluish, pubmed-meshheading:16311240-Fluorescent Dyes, pubmed-meshheading:16311240-Humans, pubmed-meshheading:16311240-Mammary Neoplasms, Animal, pubmed-meshheading:16311240-Mice, pubmed-meshheading:16311240-Mutation, pubmed-meshheading:16311240-Patch-Clamp Techniques, pubmed-meshheading:16311240-Rats, pubmed-meshheading:16311240-Software, pubmed-meshheading:16311240-Time Factors
pubmed:year
2006
pubmed:articleTitle
Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel.
pubmed:affiliation
Department of Physiology, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't