Venom resistance mechanisms in centipede show tissue specificity

Venomous animals utilize venom glands to secrete and store powerful toxins for intraspecific and/or interspecific antagonistic interactions, implying that tissue-specific resistance is essential for venom glands to anatomically separate toxins from other tissues. Here, we show the mechanism of tissue-specific resistance in centipedes (Scolopendra subspinipes mutilans), where the splice variant of the receptor repels its own toxin. Unlike the well-known resistance mechanism by mutation in a given exon, we found that the KCNQ1 channel is highly expressed in the venom gland as a unique splice variant in which the pore domain and transmembrane domain six, partially encoded by exon 6 (rather than 7 as found in other tissues), contain eleven mutated residues. Such a splice variant is sufficient to gain resistance to SsTx (a lethal toxin for giant prey capture) in the venom gland due to a partially buried binding site. Therefore, the tissue-specific KCNQ1 modification confers resistance to the toxins, establishing a safe zone in the venom-storing/secreting environment. [Display omitted] •A splice variant of KCNQ1 is expressed specifically in the venom gland of centipedes•The KCNQ1 splice variant probably evolved under SsTx-imposed selective pressure•A partially buried binding site in KCNQ1 conferred resistance to SsTx Wang et al. use a combination of molecular cloning, structural modeling, electrophysiology, and mutagenesis to show a mechanism of self-intoxication avoidance in centipedes, where the tissue-specific KCNQ1 modification confers resistance to the toxins.