TREK-1, an outward-rectifying potassium channel activated by stretch, is found in the myometrium of pregnant women. Decreased expression of TREK-1 near term suggests that TREK-1 may contribute to uterine quiescence during gestation. Five alternatively spliced TREK-1 variants were identified in the myometrium of mothers who delivered spontaneously preterm (<37 wk), leading to the hypothesis that these TREK-1 variants could interfere with TREK-1 function or expression. To investigate a potential role for these variants, immunofluorescence, cell surface assays, Western blots, and patch clamp were employed to study TREK-1 and TREK-1 variants expressed in HEK293T cells. The results of this study demonstrate that coexpression of TREK-1 with TREK-1 variants alters TREK-1 expression and suppresses channel function. Each variant affected TREK-1 in a disparate manner. In HEK293T cells coexpressing TREK-1 and each variant, TREK-1 membrane expression was diminished with compartmentalization inside the cell. When expressed alone, individual variants displayed channel properties that were significantly decreased compared to full-length TREK-1. In coexpression studies using patch clamp, basal TREK-1 currents were reduced by ∼64% (4.3 vs. 12.0 pA/pF) on average at 0 mV when coexpressed with each variant. TREK-1 currents that were activated by intracellular acidosis were reduced an average of ∼77% (21.4 vs. 94.5 pA/pF) at 0 mV when cells were transfected with TREK-1 and any one of the splice variants. These data correlate the presence of TREK-1 variants to reduced TREK-1 activity, suggesting a pathological role for TREK-1 variants in preterm labor.
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23 September 2015
Alternatively Spliced Human TREK-1 Variants Alter TREK-1 Channel Function and Localization
Chad L. Cowles,
Yi-Ying Wu,
Scott D. Barnett,
Michael T. Lee,
Heather R. Burkin,
Iain L.O. Buxton
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Biology of Reproduction
Vol. 93 • No. 5
November 2015
Vol. 93 • No. 5
November 2015
electrophysiology
human myometrial smooth muscle
labor
myometrium
potassium channels
pregnancy
preterm labor