The stretch-dependent potassium channel TREK-1 and its function in murine myometrium

Abstract

Non-technical summary During pregnancy the uterus must maintain a low contractile state to permit growth of the fetus and inhibt premature delivery. We show uterine smooth muscle cells express specific potassium channels (called stretch-dependent potassium channels; TREK-1). These channels are activated by stretch, stabilize resting membrane potentials of cells at negative potentials,and reduce excitability. During pregnancy the expression of TREK-1 channels increases, and this may contribute to reduced excitability. Near the onset of labour, TREK-1 expression declines, and this may promote the transition to a contractile state. Thus, our data suggest dynamic regulation of TREK-1 channel expression in the uterus contributes to the maintenance of pregnancy. Smooth muscle of the uterus stays remarkably quiescent during normal pregnancy to allow sufficient time for development of the fetus. At present the mechanisms leading to uterine quiescence during pregnancy and how the suppression of activity is relieved at term are poorly understood. Myometrial excitability is governed by ion channels, and a major hypothesis regarding the regulation of contractility during pregnancy has been that expression of certain channels is regulated by hormonal influences. We have explored the expression and function of stretch-dependent K + (SDK) channels, which are likely to be due to TREK channels, in murine myometrial tissues and myocytes using PCR, Western blots, patch clamp, intracellular microelectrode and isometric force measurements. TREK-1 is more highly expressed than TREK-2 in myometrium, and there was no detectable expression of TRAAK. Expression of TREK-1 transcripts and protein was regulated during pregnancy and delivery. SDK channels were activated in response to negative pressure applied to patches. SDK channels were insensitive to a broad-spectrum of K + channel blockers, including tetraethylammonium and 4-aminopyridine, and insensitive to intracellular Ca 2+ . SDK channels were activated by stretch and arachidonic acid and inhibited by reagents that block TREK-1 channels, L-methionine and/or methioninol. Our data suggest that uterine excitability and contractility during pregnancy is regulated by the expression of SDK/TREK-1 channels. Up-regulation of these channels stabilizes membrane potential and controls contraction during pregnancy and down-regulation of these channels induces the onset of delivery