Identification, Characterization and Function of Voltage-Gated and Two-Pore-Domain Potassium Channels in the Mouse Myometrium.

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Authors
Smith, Ryan C.
Issue Date
2007
Type
Dissertation
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en_US
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I am interested in the contractility and electrical excitability in the uterus at the level of individual uterine myocytes throughout gestation. 1 believe by determining potential targets for functional changes in uterine excitability I may be able to uncover the key player(s) in the regulation of resting membrane potential, the onset of labor, and thus uterine contractility. Potassium currents play important roles in the regulation of contraction in many muscles, including cardiac and visceral smooth muscle. By virtue of their ability to set resting membrane potential and exert inhibitory effects, the alterations in outward currents carried by voltage-gated (Kv) and two-pore-domain (K2P) potassium channels are key points of regulation in many excitable cells. Despite these facts little is known about the role of Kv or K2P potassium channels in the regulation of uterine contractility, and certainly nothing is known about the possible involvement of ß subunits and accessory proteins in the regulation of Kv channels and currents in myometrium from any species.|I have observed a potent contractile effect of the Kv channel blocker 4- aminopyridine (4-AP) in nonpregnant mouse myometrium, a response which is not mediated by nerves, the endometrium, or the large-conductance, voltage-activated potassium (BK) channel, and which disappears entirely in term pregnant myometrium. I have begun to explore the possibility that Kv channels play a role in uterine contractility. I have found numerous Kv channel a subunits expressed in nonpregnant mouse myometrium, including several known to be sensitive to 4-AP blockade. Furthermore, almost all of these Kv channel a subunits are expressed in the term-pregnant myometrium, except for Kv4.3 which disappears in term pregnant tissues, coincident with a loss in transient outward current (A-type) known to be carried by certain Kv channels including Kv4.3. In addition to these findings we have also uncovered a dramatic reduction in two of the K2P potassium channel proteins, TASK-1 and TREK-1. These protein levels are dramatically reduced, although at different time points, throughout pregnancy. TREK-1 protein reductions occur within the first 7 days of gestation and remain at significantly reduced levels throughout gestation. TASK-1 protein expression occurs later in gestation than does TREK-1 protein expression and appears to be dramatically reduced between the 15lh and 20th day of pregnancy. The reductions of specific Kv and K2P proteins gives further evidence for a potential role of each of these channel families in the regulation of uterine contractility throughout gestation and parturition.
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Creighton University
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