HSP90 inhibitors alter capsaicin- and ATP-induced currents in rat dorsal root ganglion neurons.
Heat shock proteins (HSPs) are major components of eukaryotic and prokaryotic cells with particularly high levels of expression in neurons. HSPs control protein folding, transport of proteins to and from the nucleus, incorporation of proteins into the cell membrane, and maintenance of the functional activity of several proteins involved in transcriptional control. In this study we demonstrate that inhibitors of HSP90 alter currents mediated by the ligand gated channels, P2X and VR1. P2X and VR1 are membrane receptors activated by ATP and capsaicin, respectively, and are thought to be involved in inflammation-related nociception. The HSP90 inhibitors geldanamycin (GLD), radicicol (RAD) herbimycin A (HERB) potentiated ATP induced currents, whereas only GLD altered capsaicin-induced currents in isolated DRG neurons. At low (< 1 microM) concentrations, GLD potentiated the capsaicin-induced current, while at high concentrations (10-25 microM) it inhibited it. The results suggest a potential involvement of HSPs in nociception.
McDowell
T S
TS
Department of Anesthesiology, University of Wisconsin Medical School, Madison, WI, USA.
Yukhananov
R Y
RY
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D016227:Benzoquinones; D002186:Cannabinoids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D011809:Quinones; D011955:Receptors, Drug; D018048:Receptors, Purinergic P2; D017828:Rifabutin; C020754:herbimycin; D000255:Adenosine Triphosphate; C035359:monorden; D002211:Capsaicin; C001277:geldanamycin