Abstract

Voltage-gated ion channels are transmembrane proteins that selectively permeate K⁺, Na⁺, or Ca²⁺ in response to the plasma membrane voltage changes. They play an essential role in neuronal excitability and molecular signaling in central and peripheral nervous systems. Dysfunctions of these ion channels are involved in various neurological disorders such as pain, migraine, schizophrenia, Alzheimer's disease, epilepsy, depression, etc. Thus, increasing numbers of academic and medical institutions and pharmaceutical industries have paid attention to these ion channel proteins as therapeutic targets. Consequently, a number of medicines modulating the channel functions have been being developed. Among the voltage-gated ion channel modulators, peptide neurotoxins from venomous animals such as cone snails, spiders, scorpions, and sea anemones are noticeable in that they modify voltage-gated ion channel activities in highly selective and potent manners. The distinctive selectivity and potency are based on their particularly rigid three-dimensional structures with multiple disulfide bonds, which confer strong and specific binding to a channel subtype. Varied inter-cysteine sequences further give an additional specificity. Ziconotide, blocking neuronal N-type voltage-gated Ca²⁺ channels in this mechanism, is the first FDAapproved peptide toxin for neurological diseases. Several other peptidergic neurotoxins are in preclinical or clinical phases. Here, we update knowledge on molecular and functional characteristics of the peptide neurotoxins targeting voltage-gated ion channels in the nervous system. We also discuss their current status of research and developments and their future therapeutic potentials.