The vast complexity of native heteromeric K⁺ channels is largely unexplored. Defining the composition and subunit arrangement of individual subunits in native heteromeric K⁺ channels and establishing their physiological roles is experimentally challenging. Here we systematically explored this "zone of ignorance" in molecular neuroscience. Venom components, such as peptide toxins, appear to have evolved to modulate physiologically relevant targets by discriminating among closely related native ion channel complexes. We provide proof-of-principle for this assertion by demonstrating that κM-conotoxin RIIIJ (κM-RIIIJ) from Conus radiatus precisely targets "asymmetric" K_v channels composed of three K_v1.2 subunits and one K_v1.1 or K_v1.6 subunit with 100-fold higher apparent affinity compared with homomeric K_v1.2 channels. Our study shows that dorsal root ganglion (DRG) neurons contain at least two major functional K_v1.2 channel complexes: a heteromer, for which κM-RIIIJ has high affinity, and a putative K_v1.2 homomer, toward which κM-RIIIJ is less potent. This conclusion was reached by (i) covalent linkage of members of the mammalian Shaker-related K_v1 family to K_v1.2 and systematic assessment of the potency of κM-RIIIJ block of heteromeric K⁺ channel-mediated currents in heterologous expression systems; (ii) molecular dynamics simulations of asymmetric K_v1 channels providing insights into the molecular basis of κM-RIIIJ selectivity and potency toward its targets; and (iii) evaluation of calcium responses of a defined population of DRG neurons to κM-RIIIJ. Our study demonstrates that bioactive molecules present in venoms provide essential pharmacological tools that systematically target specific heteromeric K_v channel complexes that operate in native tissues.

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