Propofol modulates agonist-induced transient receptor potential vanilloid subtype-1 receptor desensitization via a protein kinase Cepsilon-dependent pathway in mouse dorsal root ganglion sensory neurons.
BACKGROUND
The activity of transient receptor potential vanilloid subtype-1 (TRPV1) receptors, key nociceptive transducers in dorsal root ganglion sensory neurons, is enhanced by protein kinase C epsilon (PKCepsilon) activation. The intravenous anesthetic propofol has been shown to activate PKCepsilon. Our objectives were to examine whether propofol modulates TRPV1 function in dorsal root ganglion neurons via activation of PKCepsilon.


METHODS
Lumbar dorsal root ganglion neurons from wild-type and PKC& epsilon;-null mice were isolated and cultured for 24 h. Intracellular free Ca concentration was measured in neurons by using fura-2 acetoxymethyl ester. The duration of pain-associated behaviors was also assessed. Phosphorylation of PKCepsilon and TRPV1 and the cellular translocation of PKCepsilon from cytosol to membrane compartments were assessed by immunoblot analysis.


RESULTS
In wild-type neurons, repeated stimulation with capsaicin (100 nm) progressively decreased the transient rise in intracellular free Ca concentration. After desensitization, exposure to propofol rescued the Ca response. The resensitizing effect of propofol was absent in neurons obtained from PKCepsilon-null mice. Moreover, the capsaicin-induced desensitization of TRPV1 was markedly attenuated in the presence of propofol in neurons from wild-type mice but not in neurons from PKCepsilon-null mice. Propofol also prolonged the duration of agonist-induced pain associated behaviors in wild-type mice. In addition, propofol increased phosphorylation of PKCepsilon as well as TRPV1 and stimulated translocation of PKCepsilon from cytosolic to membrane fraction.


CONCLUSIONS
Our results indicate that propofol modulates TRPV1 sensitivity to capsaicin and that this most likely occurs through a PKCepsilon-mediated phosphorylation of TRPV1.
Wickley
Peter J
PJ
Department of Biological Sciences, Kent State University, Kent, Ohio, USA.
Yuge
Ryo
R
Russell
Mary S
MS
Zhang
Hongyu
H
Sulak
Michael A
MA
Damron
Derek S
DS
D018686:Anesthetics, Intravenous; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D005727:Ganglia, Spinal / Q000166:cytology* / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D010766:Phosphorylation; D015742:Propofol; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport; D011984:Sensory Receptor Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists*
D018686:Anesthetics, Intravenous; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D051744:Protein Kinase C-epsilon; D002118:Calcium; D015742:Propofol
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