title: Functional analysis of a migraine-associated TRESK K+ channel mutation.
abstract: Recent genetic and functional studies suggest that migraine may result from abnormal activities of ion channels and transporters. A frameshift mutation in the human TWIK-related spinal cord K(+) (TRESK) channel has been identified in migraine with aura patients in a large pedigree. In Xenopus oocytes, mutant TRESK subunits exert a dominant-negative effect on whole-cell TRESK currents. However, questions remain as to whether and how mutant TRESK subunits affect the membrane properties and the excitability of neurons in the migraine circuit. Here, we investigated the functional consequences of the mutant TRESK subunits in HEK293T cells and mouse trigeminal ganglion (TG) neurons. First, we found that mutant TRESK subunits exhibited dominant-negative effects not only on the size of the whole-cell TRESK currents, but also on the level of TRESK channels on the plasma membrane in HEK293T cells. This likely resulted from the heterodimerization of wild-type and mutant TRESK subunits. Next, we expressed mutant TRESK subunits in cultured TG neurons and observed a significant decrease in the lamotrigine-sensitive K(+) current, suggesting that the mutant TRESK subunits have a dominant-negative effect on currents through the endogenous TRESK channels. Current-clamp recordings showed that neurons expressing mutant TRESK subunits had a higher input resistance, a lower current threshold for action potential initiation, and a higher spike frequency in response to suprathreshold stimuli, indicating that the mutation resulted in hyperexcitability of TG neurons. Our results suggest a possible mechanism through which the TRESK mutation increases the susceptibility of migraine headache.
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Zheman
authors.initials: Z
authors.lastname: Xiao
authors.forename: Fei
authors.initials: F
authors.lastname: Ren
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Guo
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Hucheng
authors.initials: H
authors.lastname: Zhao
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Cao
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002478:Cells, Cultured; D004558:Electric Stimulation; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D015640:Ion Channel Gating / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000166:cytology; D000097573:Red Fluorescent Protein
chemical_list: D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D015221:Potassium Channels; D021122:Protein Subunits; D000097573:Red Fluorescent Protein; C476574:KCNK18 protein, human; C485184:enhanced green fluorescent protein; C413663:fluorescent protein 583
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