A-type potassium channels in pain signaling: Fundamental mechanisms and pathophysiological roles

Pain is a major clinical challenge characterized by maladaptive changes in somatosensory processing, leading to persistent hypersensitivity and limited therapeutic options. Voltage-gated A-type potassium channels have emerged as key determinants of neuronal excitability in both peripheral and central nociceptive pathways. By activating at subthreshold membrane potentials and rapidly inactivating, A-type potassium channels critically regulate action potential initiation, dendritic signal integration, and synaptic transmission, thereby acting as an intrinsic "brake" on pain signaling. A growing body of evidence demonstrates that downregulation or functional impairment of A-type potassium channel is a common mechanism underlying neuronal hyperexcitability in pain states, including neuropathic, inflammatory, and chemotherapy-induced pain. In dorsal root ganglion neurons and spinal dorsal horn circuits, reduced A-type potassium current contributes directly to mechanical allodynia, hyperalgesia, and central sensitization. These pathological changes are driven by complex regulatory processes, including inflammatory signaling cascades, transcriptional and post-transcriptional modulation, and post-translational modifications that dynamically suppress channel function. Importantly, A-type potassium channels activity is not fixed but highly context-dependent, varying across cell types, subcellular compartments, and disease conditions. Emerging evidence indicates that auxiliary subunits and associated regulatory networks play critical roles in shaping A-type potassium channels function and determining their contribution to pain processing. This complexity suggests that targeting A-type potassium channel complexes and their regulatory pathways may provide more precise and effective analgesic strategies compared with conventional approaches.This review summarizes current advances in the role of A-type potassium channels in pain mechanisms, with a focus on their contributions to neuronal hyperexcitability, regulatory networks, and disease-specific alterations. We further discuss the therapeutic potential of A-type potassium channels and highlight future directions for developing selective modulators aimed at restoring excitability balance in pain disorder.