Journal article
Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons
The Journal of neuroscience, Vol.28(19), pp.4904-4917
05/07/2008
DOI: 10.1523/JNEUROSCI.0233-08.2008
PMCID: PMC2641040
PMID: 18463244
Abstract
Phosphorylation-dependent modulation of the vanilloid receptor TRPV1 is one of the key mechanisms mediating the hyperalgesic effects of inflammatory mediators, such as prostaglandin E(2) (PGE(2)). However, little is known about the molecular organization of the TRPV1 phosphorylation complex and specifically about scaffolding proteins that position the protein kinase A (PKA) holoenzyme proximal to TRPV1 for effective and selective regulation of the receptor. Here, we demonstrate the critical role of the A-kinase anchoring protein AKAP150 in PKA-dependent modulation of TRPV1 function in adult mouse dorsal root ganglion (DRG) neurons. We found that AKAP150 is expressed in approximately 80% of TRPV1-positive DRG neurons and is coimmunoprecipitated with the capsaicin receptor. In functional studies, PKA stimulation with forskolin markedly reduced desensitization of TRPV1. This effect was blocked by the PKA selective inhibitors KT5720 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylicacid hexyl ester] and H89 (N-[2-(p-bromo-cinnamylamino)-ethyl]-5-isoquinoline-sulfon-amide 2HCl), as well as by the AKAP inhibitory peptide Ht31. Similarly, PGE(2) decreased TRPV1 desensitization in a manner sensitive to the PKA inhibitor KT5720. Both the forskolin and PGE(2) effects were strongly impaired in DRG neurons from knock-in mice that express a mutant AKAP150 lacking the PKA-binding domain (Delta36 mice). Protein kinase C-dependent sensitization of TRPV1 remained intact in Delta36 mice. The PGE(2)/PKA signaling defect in DRG neurons from Delta36 mice was rescued by overexpressing the full-length human ortholog of AKAP150 in these cells. In behavioral testing, PGE(2)-induced thermal hyperalgesia was significantly diminished in Delta36 mice. Together, these data suggest that PKA anchoring by AKAP150 is essential for the enhancement of TRPV1 function by activation of the PGE(2)/PKA signaling pathway.
Details
- Title: Subtitle
- Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons
- Creators
- Katrin Schnizler - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USALeonid P ShutovMichael J Van KaneganMichelle A MerrillBlake NicholsG Stanley McKnightStefan StrackJohannes W HellYuriy M Usachev
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.28(19), pp.4904-4917
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.0233-08.2008
- PMID
- 18463244
- PMCID
- PMC2641040
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- R01 GM032875 / NIGMS NIH HHS R01 NS054614-01A1 / NINDS NIH HHS R01 GM032875-23 / NIGMS NIH HHS R56 NS056244 / NINDS NIH HHS R01 NS043254 / NINDS NIH HHS NS054614 / NINDS NIH HHS R01 NS035563 / NINDS NIH HHS NS035563 / NINDS NIH HHS P01 DA015916 / NIDA NIH HHS R01 NS054614 / NINDS NIH HHS GM32875 / NIGMS NIH HHS NS043254 / NINDS NIH HHS R01 NS056244 / NINDS NIH HHS DA015916 / NIDA NIH HHS NS056244 / NINDS NIH HHS
- Language
- English
- Date published
- 05/07/2008
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9984040367202771
Metrics
13 Record Views