Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit.
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Authors
Nahorski, Michael S
Hockley, James RF
Lu, Van B
Ison, Gillian
Pattison, Luke
Callejo, Gerard
Stouffer, Kaitlin
Fletcher, Emily
Brown, Christopher
Wheeler, Daniel
Ernfors, Patrik
Menon, David
Publication Date
2020-07-21Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
32
Issue
3
Pages
107941
Language
eng
Type
Article
This Version
AM
Physical Medium
Print
Metadata
Show full item recordCitation
Lee, M., Nahorski, M. S., Hockley, J. R., Lu, V. B., Ison, G., Pattison, L., Callejo, G., et al. (2020). Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit.. Cell Rep, 32 (3), 107941. https://doi.org/10.1016/j.celrep.2020.107941
Abstract
By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant KV6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of KV2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (KV6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express KV2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing KV6.4-Met419, the voltage dependence of inactivation for KV2.1 is more depolarized compared with neurons overexpressing KV6.4. Finally, KV6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that KV6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.
Keywords
Uterus, Ganglia, Spinal, Nociceptors, Cell Membrane, Subcellular Fractions, Animals, Mice, Inbred C57BL, Humans, Labor Pain, Potassium Channels, Voltage-Gated, Protein Subunits, Analgesics, Cohort Studies, Emotions, Cognition, Pain Threshold, Ion Channel Gating, Amino Acid Sequence, Base Sequence, Pregnancy, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Alleles, Models, Biological, Adult, Female, Male, Shab Potassium Channels, Sensory Receptor Cells, Protein Multimerization
Sponsorship
MCL, DKM, DW, and CGW acknowledge funding from Addenbrooke’s Charitable Trust and the NIHR Cambridge Biomedical Research Centre. MN was funded by the Wellcome Trust (200183/Z/15/Z); JH and ESS by a Rosetrees Postdoctoral Grant (A1296) and the BBSRC (BB/R006210/1); GC and ESS by Versus Arthritis Grants (RG21973); VBL and FR by the Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z) and a joint MRC programme within the Metabolic Diseases Unit (MRC_MC_UU_12012/3). EF, GI and CB were funded by the Cambridge NIHR Biomedical Research Centre Integrative Genomics theme and LAP by a BBSRC-funded studentship (BB/M011194/1).
Funder references
Biotechnology and Biological Sciences Research Council (BB/R006210/1)
Arthritis Research UK (11600/21973)
Rosetrees Trust (A1296)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
Medical Research Council (MC_UU_12012/3)
Medical Research Council (MR/J012742/1)
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2020.107941
This record's URL: https://www.repository.cam.ac.uk/handle/1810/307545
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