Contribution of coupling between human myometrial β2-adrenoreceptor and the BKCachannel to uterine quiescence

Abstract

The β2-adrenergic receptor (β2-AR) and the large-conductance Ca2+-activated K+(BKCa) channel have been shown, separately, to be involved in mediating uterine relaxation. Our recent studies reveal that the levels of both β2-AR and BKCachannel proteins in pregnant human myometrium decrease by ∼50% after the onset of labor. We present direct evidence in support of a structural and functional association between the β2-AR and the BKCachannel in pregnant human myometrium. Localization of both proteins is predominantly plasmalemmal, with 60% of β2-AR colocalizing with the BKCachannel. Coimmunoprecipitation studies indicate that BKCaand β2-AR are structurally linked by direct protein-protein interactions. Functional correlation was confirmed by experiments of human myometrial contractility in which the BKCachannel blocker, paxilline, significantly antagonized the relaxant effect of the β2-AR agonist ritodrine. These novel findings provide an insight into the coupling between the β2-AR and BKCachannel and may have utility in the application of this signaling cascade for therapeutic potential in the management of preterm labor.