Inhibition of CaT1 channel activity by a noncompetitive IP3 antagonist.
A newly cloned, human epithelial Ca2+ transport protein (CaT1) was expressed in Xenopus laevis oocytes, and its single channel characteristics were examined. The CaT1 channel shows a strong dependence upon hyperpolarizing voltages, being activated by very negative voltages. The probability of channel opening and mean open times increase substantially at more negative voltages in the range of -90 to -160 mV. In addition, CaT1 channel activity was markedly inhibited by micromolar levels of a noncompetitive antagonist of the IP3 receptor originally isolated from a marine sponge, Xestospongin C. This inhibitory effect could be mediated indirectly via the binding of Xestospongin C to the inositol-trisphosphate (IP3) receptor or, alternatively, by a direct action on the CaT1 channel itself. Independent of its mechanism of action in inhibiting CaT1, Xestospongin C will provide a useful tool for elucidating the physiological role(s) of this novel epithelial Ca2+ channel.
Vassilev
P M
PM
Endocrine-Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Peng
J B
JB
Johnson
J
J
Hediger
M A
MA
Brown
E M
EM
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology*; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050916:TRPV Cation Channels; D014982:Xenopus laevis
D015220:Calcium Channels; D002614:Chelating Agents; D004791:Enzyme Inhibitors; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C120776:TRPV6 channel; C108644:xestospongin A; D004533:Egtazic Acid; D004492:Edetic Acid; C026060:N-(hydroxyethyl)ethylenediaminetriacetic acid