Ca2+ channel antagonist U-92032 inhibits both T-type Ca2+ channels and Na+ channels in hippocampal CA1 pyramidal neurons.
The effects of 7-[[4-[bis(4-fluorophenyl)-methyl]-1-piperazinyl]methyl] -2-[(2-hydroxyethyl)amino] 4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one (U-92032), a newly described Ca2+ channel blocker, on voltage-gated ionic currents were measured. Whole cell voltage-clamp records were obtained from acutely isolated CA1 hippocampal pyramidal neurons from 7- to 14-day-old rats. Dimethyl sulfoxide, at either 0.01% or 0.1%, partially inhibited T-type Ca2+ currents (approximately 20% inhibition) but not high-voltage-activated (HVA) Ca2+ currents. Ethanol (0.2%) did not affect Ca2+ currents. U-92032 selectively inhibited T-type Ca2+ currents (median inhibiting concentration approximately 500 nM). HVA Ca2+ currents were less sensitive, with approximately 75% of the current resistant at 10 microM. Inhibition of Ca2+ currents was reversible. U-92032 inhibited Na+ currents at concentrations similar to those required for T-type currents (> 33% block at 1 microM). Block of Na+ currents took several minutes to develop and was irreversible. Voltage-gated K+ currents were insensitive to U-92032 (1 or 10 microM). These results indicate that U-92032 inhibits both T-type Ca2+ channels and Na+ channels, constraining its utility in certain studies. Among Ca2+ channels, however, U-92032 should prove a useful tool for distinguishing physiological contributions of T-type channels.
Avery
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RB
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Johnston
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D
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010879:Piperazines; D015222:Sodium Channels; C086422:U 92032; D014334:Tropolone