Kv4.2 Channels at the Crossroads of Excitability, Plasticity, and Synaptic Signaling

Kv4.2 channels, principal mediators of the neuronal A-type K+ current, are emerging as multifunctional regulators of excitability, plasticity, and synaptic signaling. Beyond their canonical role in shaping backpropagating action potentials, Kv4.2 channels integrate diverse signaling modalities through interactions with calcium channels, scaffolding and auxiliary proteins (DPP6, KChIPs), and posttranslational regulators such as Pin1 and UBE3A. These interactions create a context-dependent network that allows Kv4.2 to function as a molecular break, stabilizing excitability under resting conditions and facilitating plasticity and learning when modulated. Recent advances in molecular and genetic tools are transforming how Kv4.2 can be studied. Next-generation genetically encoded inhibitors, for instance membrane-tethered toxins, offer cell-specific modulation of the channel. Complementary genetically encoded potassium indicators provide important steps toward real-time optical monitoring of potassium dynamics, although improvements remain necessary. After a period of diminished attention, the Kv4.2 channel is reemerging as a significant focus of scientific investigation. Recent breakthroughs, coupled with next-generation technologies, are bound to unravel the complex and multifaceted roles of Kv4.2.