The molecular mechanisms underlying uterine smooth muscle excitation during pregnancy are unknown, and this deficit has hampered the development of effective therapies for uterine dysfunction. The maintenance of uterine quiescence during pregnancy requires suppression of myometrial smooth muscle cell (MSMC) excitability until parturition. The large conductance Ca2+-activated K+ channel (maxi-K) contributes to this suppression by mediating a potent repolarizing current that dampens MSMC excitability. This channel's ability to alter MSMC excitability and uterine contractile patterns during the stages of pregnancy appears to rely on distinct molecular mechanisms that dictate channel localization and activity. In both human and mouse, isoforms of the maxi-K channel are upregulated during pregnancy to promote uterine quiescence;the various isoforms differ in their sensitivity to intracellular regulators and potentially also in their localization to distinct plasma membrane microdomains (including lipid rafts and caveolae) in which signaling molecules and their effector proteins are co-localized. The physiological importance of the maxi-K channel's role in regulating contractile activity is supported by our preliminary data showing that maxi-K knockout mice exhibit an increased frequency of uterine contraction. In spite of the strong evidence in support of the notion that the maxi-K channel modulates uterine excitability, the basic mechanisms involved in its regulation remain largely uncharacterized. The objective of this proposal is to define the distinct contributions of the maxi-K channel to myometrial excitability based on the working central hypothesis that this channel is dynamically regulated throughout pregnancy to promote uterine quiescence. Indeed, our preliminary studies in human myometrium demonstrate that maxi-K channels are localized in caveolar microdomains and transition from one caveolar compartment (cav-1/2) to another (cav-3) after the onset of labor contractions. We will test our hypothesis in two specific aims: 1) To establish how maxi-K channels are targeted to specific caveolar domains and the functional impact of the targeting on K+ channel activity in human myometrial smooth muscle cells and 2) To determine the contribution of the maxi-K channel to uterine excitability and contractility during pregnancy. This proposal aims to identify the ionic mechanisms that regulate the transition from quiescence to contraction during pregnancy in order to provide a biological basis for therapies designed to modulate uterine excitability.
This proposal contributes to improving reproductive health by focusing on K+ channel alterations, which may contribute to certain pathophysiological conditions such as preterm labor and post-term labor. In the muscle layer of the uterus, expression or activity of K+ channels can lead to abnormal uterine contractions. Knowledge gained from this proposal will help determine whether the modulation of K+ channel expression and function could be used to alleviate uterine dysfunction.
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