Regulation of BK channels in smooth muscle

Regulation of BK channel activity in myometrial and uterine vascular smooth muscle during pregnancy

Ion channel activity is responsible for changes in the membrane potential in excitable cells; potassium channels play an important role in both setting resting membrane potential and in attenuating excitation in smooth muscle cells (SMC). One channel in particular, the large conductance voltage- and Ca2+-activated potassium (BK) channel is widely expressed in several SMC types and has an established role in maintaining smooth muscle relaxation by buffering Ca2+-mediated SMC depolarization and constriction.  Numerous mechanisms of regulation of BK channel activity have been described.  Our overall goal is to understand the mechanisms by which BK channels are regulated in myometrial and vascular SMCs to help maintain uterine quiescence and increase uterine artery (UA) blood flow, respectively, during pregnancy. Specifically, we study: 1) the dynamics of BK binding to modulatory proteins in the myometrium and uterine artery during pregnancy; 2) how intrinsic properties of BK alter its association with modulatory proteins; and 3) how these modulatory proteins alter channel function and myometrial/vascular excitability.  To understand how BK channel modulates SMC excitability during pregnancy, we are conducting two main lines of investigation:

1. Regulation of BK channel in myometrium during pregnancy
The ability of BK to alter myometrial SMC excitability and uterine contractility during pregnancy appears to rely on both its localization and activity. Recent proteomic studies have identified novel binding partners of the BK channel in multiple tissues and species, but how these proteins affect BK channel characteristics has not been fully determined.  We are investigating how these interacting proteins modulate BK channel expression, localization and activity in myometrial smooth muscle throughout pregnancy.

2. The role and regulation of BK channel in the UA during pregnancy
The UA undergoes marked vasodilation during pregnancy to provide an appropriate supply of maternal blood to the fetus; however, the underlying mechanisms for this vascular remodeling remain unclear. Regulation of vascular reactivity is key to modulate blood flow, thus regulation of vascular SMC excitability is a putative mechanism for increasing blood flow in vascular beds.  BK participates in the maintenance of myogenic vascular tone by buffering depolarization and vasoconstriction in response to activation of voltage-dependent Ca2+ channels.  BK expression and activity is increased during pregnancy in the UA and inhibiting BK channels reduces basal uterine blood flow. Despite the presence of this channel in the UA, its role and regulation during pregnancy and how it contributes to vasodilation are unknown. We are studying the expression of different auxiliary subunits in UA during pregnancy and how they modulate BK activity.