The splice variants of TREK-1 act as dominant-negative suppressors of human uterine relaxation: Implications for preterm labor
type: CreativeWork
description: Human myometrium plays a pivotal role during pregnancy remaining quiescent during fetal development while eventually producing the forceful contractions necessary for parturition. The complex mechanism of maintaining uterine quiescence and triggering contraction is unclear. Spontaneous or unexplained preterm labor (PTL) accounts for approximately 45% of preterm birth (PTB) which results in infant death every 30 seconds globally. Two-pore domain potassium channels (K2P) are an emerging family of ion channels; these K2P channels participate in the regulation of excitable cells through maintaining resting membrane potential by polarizing the plasma membrane. The aberrant regulation of K2P channels may switch the cells from a resting state to one of excitation. TREK-1, a member of the K2P channel family, has previously been shown to exhibit elevated expression in pregnant human myometrium during gestation. In this study, three splice variants of intact human TREK-1 were identified in myometrium. For the first time, five non-conducting splice variants of TREK-1 were identified in preterm laboring and non-laboring myometrium, and were named as SV-1 to SV-5 due to the number of deleted exons. The exon skipping contributes to heavily truncated proteins with defective TREK-1 channel properties. Quantitative real-time PCR provided evidence of elevated expression of SV-5 in preterm labor, while TREK-1 was down-regulated. The up-regulation of SV-1, SV-3 and SV-5 are seen in preterm non-laboring myometrium.Alternative splicing has been shown to generate variants that can interfere with TREK-1 channel activity. Each individual splice variant was determined to be dominant-negative suppressors of TREK-1. The cellular distribution of TREK-1 was altered by each splice variant, which caused reduced membrane TREK-1 expression. Electrophysiological experiments confirmed the direct interaction between TREK-1 and each splice variant in basic and intracellular acidic conditions. Individual…
abstract: Human myometrium plays a pivotal role during pregnancy remaining quiescent during fetal development while eventually producing the forceful contractions necessary for parturition. The complex mechanism of maintaining uterine quiescence and triggering contraction is unclear. Spontaneous or unexplained preterm labor (PTL) accounts for approximately 45% of preterm birth (PTB) which results in infant death every 30 seconds globally. Two-pore domain potassium channels (K2P) are an emerging family of ion channels; these K2P channels participate in the regulation of excitable cells through maintaining resting membrane potential by polarizing the plasma membrane. The aberrant regulation of K2P channels may switch the cells from a resting state to one of excitation. TREK-1, a member of the K2P channel family, has previously been shown to exhibit elevated expression in pregnant human myometrium during gestation. In this study, three splice variants of intact human TREK-1 were identified in myometrium. For the first time, five non-conducting splice variants of TREK-1 were identified in preterm laboring and non-laboring myometrium, and were named as SV-1 to SV-5 due to the number of deleted exons. The exon skipping contributes to heavily truncated proteins with defective TREK-1 channel properties. Quantitative real-time PCR provided evidence of elevated expression of SV-5 in preterm labor, while TREK-1 was down-regulated. The up-regulation of SV-1, SV-3 and SV-5 are seen in preterm non-laboring myometrium.Alternative splicing has been shown to generate variants that can interfere with TREK-1 channel activity. Each individual splice variant was determined to be dominant-negative suppressors of TREK-1. The cellular distribution of TREK-1 was altered by each splice variant, which caused reduced membrane TREK-1 expression. Electrophysiological experiments confirmed the direct interaction between TREK-1 and each splice variant in basic and intracellular acidic conditions. Individual…
author: Wu, Yi-Ying
keywords: myometrial smooth muscle, pregnancy, preterm labor, splice variants, TREK-1, uterus
date published: 2013
date modified: 2026-07-27T21:46:41Z
provider: University of Nevada - Reno
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Nevada - Reno

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11714/3230