Date of Award

Winter 12-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Uterine contractions are tightly regulated throughout pregnancy, remaining relatively quiescent for the majority of pregnancy to promote fetal development, while becoming highly activated at term to effectively expel the fetus. Contractions are coordinated through electrical and mechanical coupling of myometrial smooth muscle cells (MSMCs). Ion channel activity, which alters the electrical activity of MSMCs, can directly affect the contraction profile. Thus there is great interest in the field of reproduction to understand which ion channels regulate uterine excitability, and particularly how they may enable the transition from uterine quiescence to uterine activation for labor. The focus thus far has been primarily on Ca2+ and K+ channels, however, in these studies, we identified the expression of a novel Na+ leak channel (NALCN) in the human and mouse myometrium that has a direct effect on uterine excitability. In the human myometrium, NALCN contributes to a Gd3+-sensitive, Na+-dependent leak current. To study its role in vivo, we created a smooth muscle specific NALCN knockout mouse. These mice had reduced myometrial excitability exemplified by shortening of action potential bursts, and an increased rate of prolonged and dysfunctional labor. Further implicating a role for NALCN in parturition, we found that NALCN protein levels were negatively regulated by progesterone, an important hormone in sustaining uterine quiescence, and that progesterone upregulates a novel, glycosylated isoform of NALCN. Our findings are significant in that we found NALCN contributes to the myometrial action potential, and that Na+ channel contributions are important for successful labor outcomes.

Language

English (en)

Chair and Committee

Sarah K. England

Committee Members

Jeanne M. Nerbonne, Robert P. Mecham, Kelle H. Moley, Thomas J. Baranski

Comments

Permanent URL: https://doi.org/10.7936/K7F76B03

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