Scorpion alpha-like toxins, toxic to both mammals and insects, differentially interact with receptor site 3 on voltage-gated sodium channels in mammals and insects

alpha-Like toxins, a unique group designated among the scorpion alpha-toxin class that inhibit sodium channel inactivation, are highly toxic to mice b ut do not compete for alpha-toxin binding to receptor site 3 on rat brain s odium channels. We analysed the sequence of a new alpha-like toxin, which w as also highly active on insects, and studied its action and binding on bot h mammalian and insect sodium channels. Action of the alpha-like toxin on i solated cockroach axon is similar to that of an alpha-toxin, and the radioa ctive toxin binds with a high affinity to insect sodium channels. Other sod ium channel neurotoxins interact competitively or allosterically with the i nsect alpha-like toxin receptor site, similarly to alpha-toxins, suggesting that the alpha-like toxin receptor site is closely related to receptor sit e 3. Conversely, on rat brain sodium channels, specific binding of I-125-al pha-like toxin could not be detected, although at high concentration it inh ibits sodium current inactivation on rat brain sodium channels. The difficu lty in measuring binding to rat brain channels may be attributed to low-aff inity binding due to the acidic properties of the alpha-like toxins that al so impair the interaction with receptor site 3. The results suggest that al pha-like toxins bind to a distinct receptor site on sodium channels that is differentially related to receptor site 3 on mammalian and insect sodium c hannels.