Inhibition of Membrane Na+ Channels by A Type Botulinum Toxin at Femtomolar Concentrations in Central and Peripheral Neurons

Min-Chul Shin; Masahito Wakita; Du-Jie Xie; Toshitaka Yamaga; Satomi Iwata; Yasushi Torii; Tetsuhiro Harakawa; Akihiro Ginnaga; Shunji Kozaki; Norio Akaike

doi:10.1254/jphs.11060FP

Full Papers

Inhibition of Membrane Na⁺ Channels by A Type Botulinum Toxin at Femtomolar Concentrations in Central and Peripheral Neurons

Min-Chul Shin, Masahito Wakita, Du-Jie Xie, Toshitaka Yamaga, Satomi Iwata, Yasushi Torii, Tetsuhiro Harakawa, Akihiro Ginnaga, Shunji Kozaki, Norio Akaike

Author information

Min-Chul Shin
Research Division for Life Sciences, Kumamoto Health Science University, Japan
Masahito Wakita
Research Division for Life Sciences, Kumamoto Health Science University, Japan
Du-Jie Xie
Research Division for Life Sciences, Kumamoto Health Science University, Japan
Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Japan
Toshitaka Yamaga
Research Division for Life Sciences, Kumamoto Health Science University, Japan
Department of Brain Science and Engineering, Kyushu Institute of Technology, Japan
Satomi Iwata
Research Division for Life Sciences, Kumamoto Health Science University, Japan
Yasushi Torii
Human Vaccine Production Department, The Chemo-Sero-Therapeutic Research Institute, Japan
Tetsuhiro Harakawa
Human Vaccine Production Department, The Chemo-Sero-Therapeutic Research Institute, Japan
Akihiro Ginnaga
Human Vaccine Production Department, The Chemo-Sero-Therapeutic Research Institute, Japan
Shunji Kozaki
Laboratory of Veterinary Epidemiology, Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Japan
Norio Akaike
Research Division for Life Sciences, Kumamoto Health Science University, Japan

Keywords: Na⁺ channel, hippocampal CA1 neuron, dorsal root ganglion (DRG) neuron, botulinum toxin, A2 type neurotoxin (A2NTX)

JOURNAL FREE ACCESS

2012 Volume 118 Issue 1 Pages 33-42

DOI https://doi.org/10.1254/jphs.11060FP

View "Advance Publication" version (December 10, 2011).

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Abstract

Recent studies have demonstrated that the botulinum neurotoxins inhibit the release of acetylcholine, glutamate, GABA, and glycine in central nerve system (CNS) neurons. The Na⁺ current (I_Na) is of major interest because it acts as the trigger for many cellular functions such as transmission, secretion, contraction, and sensation. Thus, these observations raise the possibility that A type neurotoxin might also alter the I_Na of neuronal excitable membrane. To test our idea, we examined the effects of A type neurotoxins on I_Na of central and peripheral neurons. The neurotoxins in femtomolar to picomolar concentrations produced substantial decreases of the neuronal I_Na, but interestingly the current inhibition was saturated at about maximum 50% level of control I_Na. The inhibitory pattern in the concentration–response curve for the neurotoxins differed from tetrodotoxin (TTX), local anesthetic, and antiepileptic drugs that completely inhibited I_Na in a concentration-dependent manner. We concluded that A type neurotoxins inhibited membrane Na⁺-channel activity in CNS neurons and that I_Na of both TTX-sensitive and -insensitive peripheral dorsal ganglion cells were also inhibited similarly to a maximum 40% of the control by the neurotoxins. The results suggest evidently that A2NTX could be also used as a powerful drug in treating epilepsy and several types of pain.

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