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RECEPTORS AND SIGNAL TRANSDUCTION

Contribution of coupling between human myometrial ₂-adrenoreceptor and the BK_Ca channel to uterine quiescence

Center for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, Nottingham NG7 2RD, United Kingdom

Submitted 12 May 2004 ; accepted in final form 17 August 2004

The ₂-adrenergic receptor (₂-AR) and the large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel have been shown, separately, to be involved in mediating uterine relaxation. Our recent studies reveal that the levels of both ₂-AR and BK_Ca channel 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 ₂-AR and the BK_Ca channel in pregnant human myometrium. Localization of both proteins is predominantly plasmalemmal, with 60% of ₂-AR colocalizing with the BK_Ca channel. Coimmunoprecipitation studies indicate that BK_Ca and ₂-AR are structurally linked by direct protein-protein interactions. Functional correlation was confirmed by experiments of human myometrial contractility in which the BK_Ca channel blocker, paxilline, significantly antagonized the relaxant effect of the ₂-AR agonist ritodrine. These novel findings provide an insight into the coupling between the ₂-AR and BK_Ca channel and may have utility in the application of this signaling cascade for therapeutic potential in the management of preterm labor.

₂-adrenergic receptor; myometrium; potassium channel; preterm labor; uterine contraction

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