The molecular mechanisms governing the transition of a pregnant uterus from a quiescent state during gestation to a contractile state at delivery are largely unknown, and this deficit has hampered the development of effective therapies to prevent preterm labor. An important feature of uterine contractions is that they occur spontaneously and rhythmically without neuronal or hormonal input. Thus, the uterine muscle (myometrium) must have intrinsic mechanisms to generate and pace contractions. To generate a contraction, the myometrial cell membrane slowly depolarizes (becomes less negative on the inside of the cell relative to the outside) to a threshold level, at which time the cell generates an action potential. This slow depolarization, or pacemaker potential, is vital for myometrial rhythmicity and is the result of background or “leak” currents that allow slow influx of positively charged ions.
Our laboratory discovered a Na+-dependent leak current in human myometrium and demonstrated that the Na+-leak channel, NALCN, contributes to this current.
Our current studies focus on:
- Determining the mechanism by which NALCN becomes sensitive to agents that induce contraction in human myometrial smooth muscle cells
- Determining the mechanism by which NALCN localizes to the myometrial smooth muscle plasma membrane to modulate uterine excitability