anti-calmodulins and tricyclic adjuvants in pain therapy block the trpv1 channelanti-calmodulins和三环佐剂在疼痛治疗阻止trpv1通道.pdfVIP

Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel ´ ´ 1,2,3 ´ 1 ´ ´ 1 ´ 2,4 5 ´ 6 ¨ ¨ 1 ´ 3 1 Zoltan Olah *, Katalin Josvay , Laszlo Pecze , Tamas Letoha , Norbert Babai , Denes Budai , Ferenc Otvos , Sandor Szalma , Csaba Vizler 1 Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary, 2 Acheuron Hungary Ltd., Szeged, Hungary, 3 Acheuron Pharmaceuticals Inc., San Diego, California, United States of America, 4 Department of Medical Chemistry, Faculty of General ´ ´ Medicine, University of Szeged, Szeged, Hungary, 5 Department of Experimental Zoology and Neurobiology, University of Pecs, Pecs, Hungary, 6 Department of Biology, Gyula Juh{sz Faculty of Education, University of Szeged, Szeged, Hungary Ca2+-loaded calmodulin normally inhibits multiple Ca2+-channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca2+-uptake via the vanilloid inducible Ca2+-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+- uptake at mM concentrations: calmidazolium (broad range)$trifluoperazine (narrow range).chlorpromazine/amitriptyline.- fluphenazine..W-7 and W-13 (only partially). Most likely a short