Kv6.4 as a Selective Therapeutic Target for Uterine Pain: Functional Consequences of a Rare KCNG4 Variant

Female pain remains significantly under-researched and frequently under-treated. Chronic primary pain conditions, such as migraine, fibromyalgia, and complex regional pain syndrome, affect women up to four times more often than men. Uterine-specific conditions like dysmenorrhea and endometriosis further exacerbate this disparity, significantly impacting quality of life and contributing to a growing socioeconomic burden. In 2020, the Woods lab identified a rare genetic variant (rs140124801, KV6.4-Met419) associated with reduced labor pain. Healthy women who did not request analgesia during their first delivery, despite normal sensory thresholds, were significantly enriched for this variant in the KCNG4 gene. KCNG4 encodes Kv6.4, a silent voltage-gated potassium channel subunit that modulates sensory neuron excitability through interaction with Kv2.1, a key delayed-rectifier potassium channel expressed in the central and peripheral nervous systems.