Scorpion alpha and alpha-like toxins differentially interact with sodium channels in mammalian CNS and periphery

Scorpion alpha-toxins from Leiurus quinquestriatus hebraeus, LqhII and LqhI II, are similarly toxic to mice when administered by a subcutaneous route, but in mouse brain LqhII is 25-fold more toxic. Examination of the two toxi ns effects in central nervous system (CNS), peripheral preparations and exp ressed sodium channels revealed the basis for their differential toxicity. In rat brain synaptosomes, LqhII binds with high affinity, whereas LqhIII c ompetes only at high concentration for LqhII-binding sites in a voltage-dep endent manner. LqhII strongly inhibits sodium current inactivation of brain rBII subtype expressed in HEK293 cells, whereas LqhIII is weakly active at 2 mu m, suggesting that LqhIII affects sodium channel subtypes other than rBII in the brain. In the periphery, both toxins inhibit tetrodotoxin-sensi tive sodium current inactivation in dorsal root ganglion neurons, and are s trongly active directly on the muscle and on expressed mu I channels. Only LqhII, however, induced repetitive end-plate potentials in mouse phrenic ne rve-hemidiaphragm muscle preparation by direct effect on the motor nerve. T hus, rBII and sodium channel subtypes expressed in peripheral nervous syste m (PNS) serve as the main targets for LqhII but are mostly not sensitive to LqhIII. Toxicity of both toxins in periphery may be attributed to the dire ct effect on muscle. Our data elucidate, for the first time, how different toxins affect mammalian central and peripheral excitable cells, and reveal unexpected subtype specificity of toxins that interact with receptor site 3 .