Contribution of coupling between human myometrial beta2-adrenoreceptor and the BK(Ca) channel to uterine quiescence.
The beta(2)-adrenergic receptor (beta(2)-AR) and the large-conductance Ca(2+)-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 beta(2)-AR and BK(Ca) channel proteins in pregnant human myometrium decrease by approximately 50% after the onset of labor. We present direct evidence in support of a structural and functional association between the beta(2)-AR and the BK(Ca) channel in pregnant human myometrium. Localization of both proteins is predominantly plasmalemmal, with 60% of beta(2)-AR colocalizing with the BK(Ca) channel. Coimmunoprecipitation studies indicate that BK(Ca) and beta(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 beta(2)-AR agonist ritodrine. These novel findings provide an insight into the coupling between the beta(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.
Center for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, Academic Division of Obstetrics and Gynaecology, The Medical School, Derby City General Hospital, Uttoxeter New Road, Derby DE22 3DT, UK.
Boonsri
B
Chanrachakul
Fiona
F
Broughton Pipkin
Raheela N
RN
Khan
D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009215:Myometrium / Q000378:metabolism*; D007752:Obstetric Labor, Premature / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D011247:Pregnancy; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D012312:Ritodrine / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D015149:Tocolytic Agents / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*
D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D018343:Receptors, Adrenergic, beta-2; D015149:Tocolytic Agents; C048220:paxilline; D012312:Ritodrine