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

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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.