Virol A, a toxic trans-polyacetylenic alcohol of Cicuta virosa, selectively inhibits the GABA-induced Cl(-) current in acutely dissociated rat hippocampal CA1 neurons.
The effects of virol A (VA), a toxic component of Cicuta virosa (water hemlock), on the GABA-induced Cl(-) current (I(GABA)) in acutely dissociated rat hippocampal CA1 neurons were investigated using whole-cell patch-clamp techniques. VA reversibly reduced I(GABA) and the muscimol (Mus)-induced current (I(Mus)) in a concentration-dependent manner. The IC(50) values for VA against I(GABA) and I(Mus) were 9.6x10(-7) and 9.8x10(-7) M, respectively. VA shifted the EC(50) value of I(GABA) from 6.5x10(-6) to 2.1x10(-5) M, whereas it had no effect on the maximum response, thereby suggesting that VA inhibited I(GABA) in a competitive manner. VA had no apparent effect on current-voltage relationships for I(GABA), thus indicating the lack of voltage-dependency. On the other hand, application of VA (10(-6) M) did not additionally reduce the I(GABA) suppressed by >10(-5) M picrotoxin. VA but not bicuculline accelerated the decay phase of I(GABA), as was seen with picrotoxin. Moreover, pre-application of 10(-5) M VA reduced I(GABA). VA did not inhibit that induced by glycine (10(-4) M). These results indicate that VA inhibits I(GABA) by acting both on the GABA agonist site and on the Cl(-) channel of the GABA(A) receptor-channel complex. VA is a structurally novel type of compound that selectively inhibits the GABA(A) receptor-Cl(-) channel complexes in mammalian central nervous system neurons.
Uwai
K
K
Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Miyagi, Japan.
Ohashi
K
K
Takaya
Y
Y
Oshima
Y
Y
Furukawa
K
K
Yamagata
K
K
Omura
T
T
Okuyama
S
S
D000818:Animals; D019661:Apiaceae / Q000737:chemistry*; D001667:Binding, Competitive / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D004594:Electrophysiology; D005233:Fatty Alcohols / Q000378:metabolism / Q000494:pharmacology*; D018756:GABA Antagonists / Q000378:metabolism / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010947:Plants, Toxic / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018118:Chloride Channels; D005233:Fatty Alcohols; D018756:GABA Antagonists; C425470:virol A; D005680:gamma-Aminobutyric Acid; D005998:Glycine