Gadolinium activates and sensitizes the vanilloid receptor TRPV1 through the external protonation sites.
Gadolinium is a recognized blocker of many types of cation channels, including several channels of the transient receptor potential (TRP) superfamily. In this study, we demonstrate that Gd(3+), in addition to its blocking effects, activates and potentiates the recombinant vanilloid receptor TRPV1 expressed in HEK293T cells. Whole-cell currents through TRPV1 were induced by Gd(3+) with a half-maximal activation achieved at 72 microM at +40 mV. Gd(3+), at concentrations up to 100 microM, lowered the threshold for heat activation and potentiated the currents induced by capsaicin (1 microM) and low extracellular pH (6). Higher concentrations of Gd(3+) (>300 microM) blocked the TRPV1 channel. Neutralizations of the two acidic residues, Glu600 and Glu648, which are the key residues conferring the proton-sensitivity to TRPV1, resulted in a loss of Gd(3+)-induced activation and/or a reduction in its potentiating effects. A trivalent nonlanthanide, Al(3+), that possesses much a smaller atomic mass than Gd(3+) blocked but did not activate or sensitize the TRPV1 channel. These findings indicate that Gd(3+) activates and potentiates the TRPV1 by neutralizing two specific proton-sensitive sites on the extracellular side of the pore-forming loop.
Tousova
Karolina
K
Department of Cellular Neurophysiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 14220 Prague 4, Czech Republic.
Vyklicky
Ladislav
L
Susankova
Klara
K
Benedikt
Jan
J
Vlachova
Viktorie
V
D019943:Amino Acid Substitution; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017931:DNA Primers; D004594:Electrophysiology / Q000379:methods; D005682:Gadolinium / Q000494:pharmacology*; D005822:Genetic Vectors; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D007668:Kidney; D016297:Mutagenesis, Site-Directed; D050916:TRPV Cation Channels
D017931:DNA Primers; D007473:Ion Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D005682:Gadolinium