PT - JOURNAL ARTICLE AU - Michael C. Lee AU - Michael S. Nahorski AU - James R.F. Hockley AU - Van B. Lu AU - Kaitlin Stouffer AU - Emily Fletcher AU - Gillian Ison AU - Christopher Brown AU - Daniel Wheeler AU - Patrik Ernfors AU - David Menon AU - Frank Reimann AU - Ewan St John Smith AU - C. Geoffrey Woods TI - Human labor pain is influenced by the voltage-gated potassium channel K<sub>V</sub>6.4 subunit AID - 10.1101/489310 DP - 2018 Jan 01 TA - bioRxiv PG - 489310 4099 - http://biorxiv.org/content/early/2018/12/06/489310.short 4100 - http://biorxiv.org/content/early/2018/12/06/489310.full AB - We sought Mendelian genetic influences on labor pain by studying healthy women who neither requested nor used drug-based analgesia during their first labor; a discovery cohort of 116 were exome sequenced, and an additional 80 had targeted sequencing. Thirty-three of these 196 women underwent comprehensive sensory and psychometric tests, which revealed higher experimental pain thresholds, particularly to deep somatic pressure, when compared to matched controls. We found an excess of heterozygotes carrying the rare allele SNP rs140124801 p.Val419Met in KCNG4 (encoding the voltage-gated potassium channel subunit KV6.4); 6 versus an expected 1.57, P &lt; 0.001. We show that the rare variant KV6.4-Met419 fails to traffic to the plasma membrane and, unlike KV6.4, does not modulate the voltage-dependence of KV2.1 inactivation. In vivo, we observed Kcng4 (KV6.4) to be present in 40% of retrolabelled mouse uterine sensory neurons, all of which expressed Kcnb1 (KV2.1), and over 90% of which expressed the nociceptor markers Trpv1 and Scn10a. Moreover, the voltage-dependence of inactivation for KV2.1-mediated currents is more depolarized when KV6.4-Met419 is overexpressed in mouse sensory neurons compared to when KV6.4 is overexpressed and hence expression of KV6.4-Met419 produces less excitable sensory neurons. Lastly, we show that KV6.4-Met419 has a dominant–negative effect on wild type KV6.4, consistent with the reduction of labor pain observed in the individuals of our cohort who were heterozygotes for the KCNG4 SNP rs140124801 allele. KV6.4 impacts human labor pain by modulating the function of nociceptors that innervate the uterus.One Sentence Summary Human labor pain is influenced by KCNG4/KV6.4 ion channel, which modulates the excitability of sensory neurons.