Introduction
Acid-sensitive ion channels (ASICs) are a class of proton-gated ion channels belonging to the Degenerin/Epithelial sodium channel family (Deg/ENaC) with four encoded genes: ASIC1, ASIC2, ASIC3, ASIC4. ASICs can act as selective sodium channels in the nervous system of vertebrates. In ASICs, the ASIC1 channel is responsible for transient H+ induced currents in neurons of the central nervous system, and it also involves physiological processes of learning and perception, such as pain. The main expression of Ca2+ permeability in spinal cord neurons is ASIC1a. Psalmotoxin 1 (PcTx1) is a specific ASIC1a homopolymer channel inhibitor, which significantly inhibits the inward current induced by acidic solutions.
Function
PcTx1 has an analgesic effect in a rodent model of acute pain and provides neuroprotection in a mouse model of ischemic stroke. PcTx1 not only interacts with homotrimers of extracellular ASIC1, but also interferes with channel opening and gating. At the time of binding, there is a significant shift in the activation and desensitization curves under the influence of pH. PcTx1 causes a small conformational change on the pH sensor, and it is speculated that the movement of the thumb coils 4 and 5 also indirectly affects the cation reservoir and the conductive pores. Experimental data indicates that the largest three toxin molecules can be bind to one ASIC1 trimer and provide intermolecular interactions at the PcTx1-ASIC1 interface. It has been reported that the gating modifier PcTx1 is a concept of two-way binding and motion limitation of the regulatory region.
The prospect of application
PcTx1 is considered to have high therapeutic value owing to its unique selectivity in regulating only the ASIC1 channel. This complex structure can be used as a starting template for small molecule designs that maintain PcTx1 selectivity but obtain better brain penetration. This small molecule penetrating the brain will be an ideal pharmacological tool to further confirm ASIC1 as a drug target, and pave the way for the development of new drugs against pain and various central nervous system diseases.
References:
Waldmann, R., Bassilana, F., de Weille, J., Champigny, G., Heurteaux, C., & Lazdunski, M. (1997). Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. Journal of Biological Chemistry, 272(34), 20975-20978.
Kellenberger, S., & Schild, L. (2002). Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiological reviews, 82(3), 735-767.
Wemmie, J. A., Chen, J., Askwith, C. C., Hruska-Hageman, A. M., Price, M. P., Nolan, B. C., ... & Welsh, M. J. (2002). The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron, 34(3), 463-477.
