In most species, including humans, plasma levels of 17beta-estradiol and progesterone increase during pregnancy. The elevation of female steroid hormones that accompanies the late stages of pregnancy has been linked to electrical remodeling of myometrial smooth muscle. These observations suggest that female steroid hormones can influence the activity and/or expression of ionic conductances involved in uterine smooth muscle excitability. Although it has been reported that the delivery mechanism is related to a decrease in female hormone levels, the mechanism of labor contraction has not been clearly studied in terms of ion channel expression. During pregnancy, the mass of myometrium increases dramatically, with only minimal increases in intrauterine pressure. To accomplish this, the smooth muscle of the myometrium must remain relaxed during pregnancy. Therefore, K+ conductances activated by stretch of the plasma membrane may contribute an important component of the myogenic response in the uterus. Several K+ channels participate in the regulation of resting membrane potential and repolarization of action potentials in the myometrium. Recently unique K+ channels have been reported that consist of four transmembrane segments and two-pore domains (K2P). Among K2P channels, TREK-1, TREK-2 and TRAAK have unique functional properties and represent the first cloned stretch-activated K+ channels. Previous studies suggest that female steroid hormones influence the transcriptional expression of a number of K+ channels. We will address the following specific aims in this proposal:
Aim 1, we will identify SDK channel functional expression in the murine myometrium using patch-clamp methods and will characterize the regulation of these channels by nitric oxide and its intracellular signaling mechanisms.
Aim 2, we will characterize stretch-dependent hyperpolarization and relaxation in intact myometrium using conventional microelectrode recordings, isometric force measurements and Ca2+ imaging analysis.
Aim 3, we will use molecular and protein techniques to investigate TREK-1 expression in murine myometrium in relation to native SDK channels.
Aim 4, we will characterize changes in TREK-1 expression in non-pregnant, pregnant, postpartum and ovariectomized murine models to understand the functional expression of native SDK channels under various levels of female hormones. In particular this investigation will expand the molecular mechanism of estrogen regulation of TREK-1 channels that leads to the different levels of myometrial compliance. Understanding this mechanism may allow for clinical intervention in the modulation of labor and delivery, reducing the number of premature births and subsequent disorders.
The rate of premature birth has grown by more than 30 percent in the last 20 years. In about 40 percent of all cases of preterm birth, the causes of preterm labor are unknown. Experiments outlined in this proposal are designed to evaluate changes in uterine TREK-1 channels that accompany acute and chronic changes in female steroid hormone levels to study a potential functional relationship with pregnancy and delivery mechanisms.
| Monaghan, Kevin; Baker, Salah A; Dwyer, Laura et al. (2011) The stretch-dependent potassium channel TREK-1 and its function in murine myometrium. J Physiol 589:1221-33 |
