Human keratinocytes are vanilloid resistant
| Autor: | Csaba Vizler, Kornélia Szabó, Tamás Letoha, Erzsébet Kusz, András Tóth, István Koncz, Márta Széll, Lajos Kemény, László Pecze, János Prorok, Zoltán Oláh, Katalin Jósvay, Krisztián Kaszás |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Keratinocytes
Pathology medicine.medical_specialty Cell type Resiniferatoxin TRPV1 Drug Resistance TRPV Cation Channels lcsh:Medicine Dermatology Vanilloids chemistry.chemical_compound Medicine Humans RNA Messenger lcsh:Science Cells Cultured Anesthesiology and Pain Management Skin Multidisciplinary Cell Death Dose-Response Relationship Drug business.industry musculoskeletal neural and ocular physiology lcsh:R HaCaT chemistry nervous system Capsaicin Cell culture Cancer research Nociceptor Calcium lipids (amino acids peptides and proteins) lcsh:Q Diterpenes business Research Article Neuroscience |
| Zdroj: | PLoS ONE, Vol 3, Iss 10, p e3419 (2008) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca2+-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular surgery have shown neither obvious behavioral, nor pathological side effects. Methods To address this paradox, we assessed the vanilloid sensitivity of the HaCaT human keratinocyte cell line and primary keratinocytes from skin biopsies. Results Although both cell types express TRPV1 mRNA, neither responded to vanilloids with Ca2+-cytotoxicity. Only ectopic overproduction of TRPV1 rendered HaCaT cells sensitive to low doses (1–50 nM) of vanilloids. The TRPV1-mediated and non-receptor specific Ca2+-cytotoxity ([RTX]>15 µM) could clearly be distinguished, thus keratinocytes were indeed resistant to vanilloid-induced, TRPV1-mediated Ca2+-entry. Having a wider therapeutic window than capsaicin, RTX was effective in subnanomolar range, but even micromolar concentrations could not kill human keratinocytes. Keratinocytes showed orders of magnitudes lower TRPV1 mRNA level than sensory ganglions, the bona fide therapeutic targets in human pain management. In addition to TRPV1, TRPV1b, a dominant negative splice variant was also noted in keratinocytes. Conclusion TRPV1B expression, together with low TRPV1 expression, may explain the vanilloid paradox: even genuinely TRPV1 mRNA positive cells can be spared with therapeutic (up to micromolar) doses of RTX. This additional safety information might be useful for planning future human clinical trials. |
| Databáze: | OpenAIRE |
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