Microdomain-resolved potassium channel gating as a controllable process: patient-specific excitability landscapes, attractor stability, and closed-loop therapeutic optimization.

INTRODUCTION: Potassium conductances regulate neuronal excitability across heterogeneous disorders, controlling thresholds, repolarization, adaptation, and bursting at a low energetic cost. However, translating this biology into therapeutic stratification remains incompletely validated. This reviewdistinguishes established potassium-channel mechanisms from conceptual integration and future-facing translational proposals.

AREAS COVERED: Based on the literature identified through searches for PubMed/MEDLINE, Embase, Web of Science Core Collection, and Scopus (inception-May 2026), this review advances an 'excitability fingerprint' translational framework, linking microdomain-resolved gating to network stability and future biomarker-enriched therapeutic development. Voltage-gated potassium channels, big- and small-conductance Ca2+ -activated K+ channels , inwardly rectifying , ATP-sensitive and two-pore domain potassium channels are gated by phosphatidylinositol 4,5-bisphosphate (PIP2), Ca2+, redox, and pH across neural and glial microdomains. A tri-axial fingerprint is defined: electroencephalography (EEG)/high-frequency oscillation (HFO) and transcranial magnetic stimulation (TMS) metrics; microdomain tone (PIP2/redox); and astroglial K+ buffering, modulated by age, sex, genetics, and metabolic-inflammatory comorbidities. Biomarker-anchored titration uses electrophysiology, molecular panels of redox and acid-base status, and patient-derived induced pluripotent stem cell (iPSC) assays of PIP2-dependent M-current rescue.

EXPERT OPINION: Fingerprint-guided K+ modulation can compress time-to-response and manage network-level risk, supporting standardized pipelines, practical microdomain assays, and response-adaptive trials to implement individualized therapeutic windows.