The Na+/Ca2+ exchange inhibitor KB-R7943 potently blocks TRPC channels.
Na(+)/Ca(2+) exchangers (NCXs) and members of the canonical transient receptor potential (TRPC) channels play an important role in Ca(2+) homeostasis in heart and brain. With respect to their overlapping expression and their role as physiological Ca(2+) influx pathways a functional discrimination of both mechanisms seems to be necessary. Here, the effect of the reverse-mode NCX inhibitor KB-R7943 was investigated on different TRPC channels heterologously expressed in HEK293 cells. In patch-clamp recordings KB-R7943 potently blocked currents through TRPC3 (IC(50)=0.46 microM), TRPC6 (IC(50)=0.71 microM), and TRPC5 (IC(50)=1.38 microM). 1-Oleoyl-2-acetyl-sn-glycerol-induced Ca(2+) entry was nearly completely suppressed by 10 microM KB-R7943 in TRPC6-transfected cells. Thus, KB-R7943 is able to block receptor-operated TRP channels at concentrations which are equal or below those required to inhibit reverse-mode NCX activity. These data further suggest that the protective effects of KB-R7943 in ischemic tissue may, at least partly, be due to inhibition of TRPC channels.
Kraft
Robert
R
Carl-Ludwig-Institute for Physiology, University Leipzig, Liebigstr. 27, 04103 Leipzig, Germany. robert.kraft@medizin.uni-lepzig.de
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004075:Diglycerides / Q000037:antagonists & inhibitors; D004553:Electric Conductivity; D006801:Humans; D051379:Mice; D018408:Patch-Clamp Techniques; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors*; D000074287:TRPC6 Cation Channel; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D004075:Diglycerides; D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; C112021:Trpc5 protein, mouse; C038237:1-oleoyl-2-acetylglycerol; D013890:Thiourea; D002118:Calcium