Linked Life Data

14506258

Source:http://linkedlifedata.com/resource/pubmed/id/14506258

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
2003-12-8
pubmed:abstractText
Proinflammatory prostaglandin E2 is known to sensitize sensory neurons to noxious stimuli. This sensitization is mediated by the cAMP-dependent protein kinase (PKA) signal pathway. The capsaicin receptor TRPV1, a non-selective cation channel of sensory neurons involved in the sensation of inflammatory pain, is a target of PKA-mediated phosphorylation. Our goal was to investigate the influence of PKA on Ca(2+)-dependent desensitization of capsaicin-activated currents. By using site-directed mutagenesis, we created point mutations at PKA consensus sites and studied wild-type and mutant channels transiently expressed in HEK293t cells under whole-cell voltage clamp. We found that forskolin, a stimulator of adenylate cyclase, decreased desensitization of TRPV1. The selective PKA inhibitor H89 inhibited this effect. Mimicking phosphorylation at PKA consensus sites by replacing Ser-6, Ser-116, Thr-144, Thr-370, Ser-502, Ser-774, or Ser-820 with aspartate resulted in five mutations (S116D, T144D, T370D, S774D, and S820D) that exhibited decreased desensitization as well. However, disrupting phosphorylation by replacing respective sites with alanine resulted in four mutations (S6A, T144A, T370A, and S820A) with desensitization properties resembling those of the aspartate mutations. Significant changes in relative permeabilities for Ca2+ over Na+ or in capsaicin sensitivity could not explain changes in desensitization properties of mutant channels. In mutations S116A, S116D, T370A, and T370D, pretreatment of cells with forskolin did not reduce desensitization as compared with wild-type and other mutant channels. We conclude that Ser-116 and possibly Thr-370 are the most important residues involved in the mechanism of PKA-dependent reduction of desensitization of capsaicin-activated currents.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
50080-90
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:14506258-Animals, pubmed-meshheading:14506258-Aspartic Acid, pubmed-meshheading:14506258-Binding Sites, pubmed-meshheading:14506258-Calcium, pubmed-meshheading:14506258-Capsaicin, pubmed-meshheading:14506258-Cell Line, pubmed-meshheading:14506258-Cell Membrane, pubmed-meshheading:14506258-Cyclic AMP, pubmed-meshheading:14506258-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:14506258-DNA, Complementary, pubmed-meshheading:14506258-Dose-Response Relationship, Drug, pubmed-meshheading:14506258-Electrophysiology, pubmed-meshheading:14506258-Enzyme Activation, pubmed-meshheading:14506258-Humans, pubmed-meshheading:14506258-Models, Biological, pubmed-meshheading:14506258-Mutagenesis, Site-Directed, pubmed-meshheading:14506258-Mutation, pubmed-meshheading:14506258-Phosphorylation, pubmed-meshheading:14506258-Plasmids, pubmed-meshheading:14506258-Point Mutation, pubmed-meshheading:14506258-Protein Binding, pubmed-meshheading:14506258-Rats, pubmed-meshheading:14506258-Receptors, Drug, pubmed-meshheading:14506258-Serine, pubmed-meshheading:14506258-Threonine, pubmed-meshheading:14506258-Transfection
pubmed:year
2003
pubmed:articleTitle
Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway.
pubmed:affiliation
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't