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Inhibitory effects of bifemelane on brain Ca2+ channel subtypes expressed in Xenopus oocytes
M Kinoshita1, S Kaneko, T Yasuno
1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Abstract:
Effects of the cerebroprotective agent bifemelane on voltage-dependent Ca2+ channel currents were evaluated in Xenopus oocytes expressing specific Ca2+-channel subtypes. Extracellular perfusion of bifemelane showed a dose-dependent blocking action on both N-type and Q-type Ca2+ channels, but not on cardiac L-type Ca2+ channels expressed in the oocytes, and the inhibitory action on Q-type current was stronger than that on N-type current. The time course of inhibition by bifemelane was comparatively slow; a 20-min perfusion with 1 microM bifemelane was required to reduce the amplitude of the Q-type current to 80% of the control level. When bifemelane was applied intracellularly, the potency and time-course of inhibition was equivalent to that caused by the perfusion of bifemelane. The bifemelane-induced inhibition was voltage-dependent but not use-dependent in Q-type channels since it was apparent at more depolarized potentials but not influenced by the interval of depolarization. These results suggest that bifemelane inhibits the opening of the specific Ca2+ channels located at nerve terminals to suppress excessive neurotransmitter release from neurons in some pathophysiological conditions such as ischemia.
Insights
Bifemelane, a cerebroprotective drug, blocks N-type and Q-type calcium channels, but not L-type. This action may prevent excessive neurotransmitter release in conditions like ischemia.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Cerebroprotective agents are crucial for managing neurological conditions.
- Voltage-dependent calcium channels play a key role in neurotransmitter release.
- Understanding drug interactions with specific calcium channel subtypes is vital for therapeutic development.
Purpose of the Study:
- To investigate the effects of bifemelane on various voltage-dependent calcium channel subtypes.
- To elucidate the mechanism of bifemelane's action on neuronal calcium channels.
Main Methods:
- Utilized Xenopus oocytes expressing specific calcium channel subtypes (N-type, Q-type, L-type).
- Applied bifemelane extracellularly and intracellularly to assess dose-dependent and time-course effects.
- Investigated voltage-dependence and use-dependence of bifemelane's inhibitory action.
Main Results:
- Bifemelane demonstrated dose-dependent blockade of N-type and Q-type calcium channels.
- Cardiac L-type calcium channels were unaffected by bifemelane.
- Inhibition of Q-type current was more potent than N-type, with a slow onset.
- Bifemelane's inhibition was voltage-dependent but not use-dependent on Q-type channels.
Conclusions:
- Bifemelane selectively inhibits specific calcium channels at nerve terminals.
- This inhibition mechanism likely suppresses excessive neurotransmitter release.
- Bifemelane shows potential therapeutic value in conditions like ischemia.