Human labor pain is influenced by the voltage-gated potassium channel KV6.4 subunit

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 K V 6.4); 6 versus an expected 1.57, P V 6.4Met419 fails to traffic to the plasma membrane and, unlike K V 6.4, does not modulate the voltage−dependence of K V 2.1 inactivation. In vivo, we observed Kcng4 (K V 6.4) to be present in 40% of retrolabelled mouse uterine sensory neurons, all of which expressed Kcnb1 (K V 2.1), and over 90% of which expressed the nociceptor markers Trpv1 and Scn10a. Moreover, the voltage−dependence of inactivation for K V 2.1 mediated currents is more depolarized when K V 6.4Met419 is overexpressed in mouse sensory neurons compared to when K V 6.4 is overexpressed and hence expression of K V 6.4Met419 produces less excitable sensory neurons. Lastly, we show that K V 6.4Met419 has a dominant negative effect on wild type K V 6.4, consistent with the reduction of labor pain observed in the individuals of our cohort who were heterozygotes for the KCNG4 SNP rs140124801 allele. K V 6.4 impacts human labor pain by modulating the function of nociceptors that innervate the uterus.