Heteromeric Kv1.2 channels counteract persistent sodium currents in proprioceptive DRG neurons

Voltage-gated potassium channels (VGKCs) comprise one of the largest, most diverse and complex families of ion channels. Approximately 70 genes encode the alpha subunits that form homomeric VGKC channels. In addition, these subunits can form functional heteromeric channels, thus exponentially increasing the diversity of VGKCs. The functional expression and physiological role of heteromeric K-channels have remained largely unexplored due to the lack of tools to probe their functions. Conotoxins have high affinity and specificity for heteromeric combinations of K-channels and show great promise for elucidating their functions. In this work, using conotoxin kM-RIIIJ as a pharmacological probe, we explore the expression and physiological functions of heteromeric Kv1.2 channels using constellation pharmacology. We report that heteromers of Kv1.2/1.1 are highly expressed in proprioceptive neurons found in the dorsal root ganglion (DRG). Inhibition of Kv1.2/1.1 heteromers leads to an influx of calcium ions, suggesting that these channels regulate neuronal excitability. We also present evidence that Kv1.2/1.1 heteromers counteract persistent sodium currents, and that inhibiting these channels leads to tonic firing of action potentials. Additionally, kM-RIIIJ induces impaired proprioception in mice, uncovering a previously unrecognized physiological role of heteromeric Kv1.2/1.1 channels in proprioceptive sensory neurons of the DRG.