Small-Conductance Ca2+-Activated K+ Channels and Their Regulation of Excitability of Autonomic Neurons

Abstract Dyshomeostasis of the autonomic nervous system (ANS) drives chronic illnesses including hypertension, heart failure, diabetes mellitus, metabolic syndrome, Parkinson’s disease, and traumatic brain injury. Abnormal neuronal excitability within central nervous system (CNS) nuclei is a major cause of ANS dysfunction. Small-conductance calcium-activated potassium (SK) channels govern excitability in central autonomic nuclei, sustaining neuronal excitation-inhibition balance via medium afterhyperpolarization potentials (mAHP)-mediated negative feedback. This review describes SK channels’ molecular structure and electrophysiology, maps central sympathetic-parasympathetic neuroanatomical pathways, and highlights pathological impacts of the dysfunction of SK channels among the hypothalamic paraventricular nucleus (PVN) and nucleus ambiguus (NA). It also summarizes SK channels-centered regulatory approaches: epigenetics (DNA methylation, miRNA modulation), post-translational modification (phosphorylation, ubiquitination), protein interaction, metabolites, and synthetic exogenous agonists and antagonists. These results offer a theoretical basis and candidate targets to decode the neurogenic hypertension and diabetes mechanisms and facilitate bench-to-clinic translation.