Variants of stretch-activated two-pore potassium channel TREK-1 associated with preterm labor in humans. Academic Article uri icon

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abstract

  • Spontaneous preterm labor (PTL) is a uniquely human problem that results in preterm delivery of an underdeveloped fetus. The underlying cause remains elusive. The cost to societies in human suffering and treasure is enormous. The stretch-activated two pore potassium channel TREK-1 is up-regulated during gestation to term such that it may maintain uterine quiescence by hyperpolarizing the smooth muscle cell membrane. We have hypothesized that the human TREK-1 channel is involved in myometrial relaxation during pregnancy and that splice variants of the TREK-1 channel expressed in preterm myometrium are associated with preterm delivery by interaction with full-length TREK-1. We detected three wild-type human TREK-1 transcript isoforms in nonpregnant and pregnant human myometrium. Using RT-PCR, we identified five unique TREK-1 splice variants in myometrium from women in PTL. These myometrial TREK-1 variants lack either the pore or the transmembrane domains or both. In transiently transfected HEK293T cells, wild-type TREK-1 was predominantly expressed at the plasma membrane. However, individual splice variants were expressed uniformly throughout the cell. Wild-type TREK-1 was localized at the plasma membrane and cytoplasm close to the plasma membrane when coexpressed with each splice variant. Co-immunoprecipitation of FLAG epitope-tagged TREK-1 and six-His epitope-tagged splice variants using Ni bead columns successfully pulled down wild-type TREK-1. These results suggest that each of four TREK-1 splice variants interacts with full-length wild-type TREK-1 and that in vivo, such interactions may contribute to a PTL phenotype.

date/time value

  • 2012

Digital Object Identifier (DOI)

  • 10.1095/biolreprod.112.099499

PubMed Identifier

  • 22811574

volume

  • 87

number

  • 4

keywords

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Female
  • Genetic Association Studies
  • HEK293 Cells
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Obstetric Labor, Premature
  • Potassium Channels, Tandem Pore Domain
  • Pregnancy
  • Protein Isoforms
  • Sequence Homology, Amino Acid
  • Transfection
  • Young Adult