Anticonvulsants but not general anesthetics have differential blocking effects on different T-type current variants.
The sensitivity to anticonvulsants and anesthetics of Ca(2+) currents arising from alpha1G and alpha1H 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 alpha1G current completely but with weaker affinity ( approximately 140 microM). Among different cells, alpha1H current exhibited either of two responses to phenytoin. In one subpopulation of cells, phenytoin produced a partial, higher affinity block (IC(50) approximately 7.2 microM, maximum block approximately 43%) similar to that in DRG neurons. In other cells, phenytoin produced complete, but lower affinity, blockade (IC(50) approximately 138 microM, maximum block approximately 89%). Another anticonvulsant, alpha-methyl-alpha-phenylsuccinimide (MPS), blocked DRG current partially, but blocked both alpha1G and alpha1H currents completely with weaker affinity ( approximately 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 alpha1G current by anesthetics had the following order of potency: propofol (IC(50) approximately 20.5 microM) > etomidate ( approximately 161 microM) = octanol ( approximately 160 microM) > isoflurane ( approximately 277 microM) > ketamine ( approximately 1.2 mM), comparable with results on DRG T currents. Barbiturates completly blocked alpha1G currents with potency [thiopental ( approximately 280 microM), pentobarbital ( approximately 310 microM), phenobarbital ( approximately 1.54 mM)] similar to that in DRG cells. The effects of propofol, octanol, and pentobarbital on alpha1H currents were indistinguishable from effects on alpha1G currents.
Todorovic
S M
SM
Washington University School of Medicine, Department of Anesthesiology, St. Louis, MO 63110, USA.
Perez-Reyes
E
E
Lingle
C J
CJ
D018681:Anesthetics, General / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001463:Barbiturates / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D013388:Succinimides / Q000494:pharmacology
D018681:Anesthetics, General; D000927:Anticonvulsants; D001463:Barbiturates; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D013388:Succinimides; C032620:succinimide; D010672:Phenytoin; D007530:Isoflurane