KCNS1 encodes a potassium channel regulatory subunit that modulates the delayed rectifier voltage-gated potassium channels KCNB1 and KCNB2 by altering their kinetics, expression levels, and voltage-dependent inactivation. While unable to form functional channels independently, KCNS1 assembles into functional heterotetrameric channels with KCNB1 and KCNB2. The gene is predominantly expressed in myelinated sensory neurons, including Aδ-fiber nociceptors and Aβ mechanoreceptors in dorsal root ganglia and spinal dorsal horn 1. KCNS1 variants influence pain phenotypes across multiple contexts. A meta-analysis identified the rs734784 A>G variant as marginally increasing chr20 postsurgical pain risk 2, and genetic analyses indicate KCNS1 variation predicts pain sensitivity and risk for persistent pain 3. In peripheral sensory neurons, KCNS1 deletion increases basal mechanical pain sensitivity and exaggerates responses to neuropathic injury 1. The gene also shows altered expression in pathophysiological conditions: pyramidal neurons increase KCNS1 mRNA in response to elevated intracranial pressure 4, and temporal lobe epilepsy is associated with downregulated KCNS1 expression 5. Pharmacological approaches targeting potassium channels, including agents like amifampridine and dalfampridine that enhance potassium channel function, represent potential therapeutic strategies for pain and neurological disorders involving KCNS1 dysfunction.