Myometrial expression of small conductance Ca2+-activated K+ channels depresses phasic uterine contraction.
Mechanisms regulating uterine contractility are poorly understood. We hypothesized that a specific isoform of small conductance Ca(2+)-activated K(+) (SK) channel, SK3, promotes feedback regulation of myometrial Ca(2+) and hence relaxation of the uterus. To determine the specific functional impact of SK3 channels, we assessed isometric contractions of uterine strips from genetically altered mice (SK3(T/T)), in which SK3 is overexpressed and can be suppressed by oral administration of doxycycline (SK3(T/T)+Dox). We found SK3 protein in mouse myometrium, and this expression was substantially higher in SK3(T/T) mice and lower in SK3(T/T)+Dox mice compared with wild-type (WT) controls. Sustained contractions elicited by 60 mM KCl were not different among SK3(T/T), SK3(T/T)+Dox, and WT mice. However, the rate of onset and magnitude of spontaneously occurring phasic contractions was muted significantly in isolated uterine strips from SK3(T/T) mice compared with those from WT mice. These spontaneous contractions were augmented greatly by blockade of SK channels with apamin or by suppression of SK3 expression. Phasic but not tonic contraction in response to oxytocin was depressed in uterine strips from SK3(T/T) mice, whereas suppression of SK3 channel expression or treatment with apamin promoted the predominance of large coordinated phasic events over tone. Spontaneous contractions and the phasic component of oxytocin contractions were blocked by nifedipine but not by cyclopiazonic acid. Our findings suggest that SK3 channels play an important role in regulating uterine function by limiting influx through L-type Ca(2+) channels and disrupting the development of concerted phasic contractile events.
Brown
Amber
A
Dept. of Physiology, College of Medicine, Univ. of South Alabama, 307 University Blvd., MSB 3074, Mobile, AL 36688, USA.
Cornwell
Trudy
T
Korniyenko
Iryna
I
Solodushko
Viktoriya
V
Bond
Chris T
CT
Adelman
John P
JP
Taylor
Mark S
MS
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction; D051379:Mice; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D010507:Periodicity; D011247:Pregnancy; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014590:Uterine Contraction; D014665:Vasodilator Agents / Q000494:pharmacology
D007211:Indoles; C496900:Kcnn3 protein, mouse; D020033:Protein Isoforms; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014665:Vasodilator Agents; D001030:Apamin; D010121:Oxytocin; D009543:Nifedipine; D004318:Doxycycline; D002118:Calcium; C000543:cyclopiazonic acid