RT Journal Article
SR Electronic
T1 Anticonvulsants But Not General Anesthetics Have Differential Blocking Effects on Different T-Type Current Variants
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 98
OP 108
DO 10.1124/mol.58.1.98
VO 58
IS 1
A1 Slobodan M. Todorovic
A1 Edward Perez-Reyes
A1 Christopher J. Lingle
YR 2000
UL http://molpharm.aspetjournals.org/content/58/1/98.abstract
AB The sensitivity to anticonvulsants and anesthetics of Ca2+currents arising from α1G and α1H subunits was examined in stably transfected HEK293 cells. For comparison, in some cases blocking effects on dorsal root ganglion (DRG) T currents were also examined under identical ionic conditions. The anticonvulsant, phenytoin, which partially blocks DRG T current, blocked α1G current completely but with weaker affinity (∼140 μM). Among different cells, α1H current exhibited either of two responses to phenytoin. In one subpopulation of cells, phenytoin produced a partial, higher affinity block (IC50 ∼7.2 μM, maximum block ∼43%) similar to that in DRG neurons. In other cells, phenytoin produced complete, but lower affinity, blockade (IC50 ∼138 μM, maximum block ∼89%). Another anticonvulsant, α-methyl-α-phenylsuccinimide (MPS), blocked DRG current partially, but blocked both α1G and α1H currents completely with weaker affinity (∼1.7 mM). These data suggest that higher affinity blockade of T-type currents by phenytoin and MPS may require additional regulatory factors that can contribute to native T-type channels. In contrast, anesthetics blocked all T current variants similarly and completely. Block of α1G current by anesthetics had the following order of potency: propofol (IC50 ∼20.5 μM) > etomidate (∼161 μM) = octanol (∼160 μM) > isoflurane (∼277 μM) > ketamine (∼1.2 mM), comparable with results on DRG T currents. Barbiturates completly blocked α1G currents with potency [thiopental (∼280 μM), pentobarbital (∼310 μM), phenobarbital (∼1.54 mM)] similar to that in DRG cells. The effects of propofol, octanol, and pentobarbital on α1H currents were indistinguishable from effects on α1G currents.