BK_Ca channel activation by membrane-associated cGMP kinase may contribute to uterine quiescence in pregnancy

Abstract

We investigated the influence of pregnancy on large-conductance calcium-activated potassium channel (BK(Ca)) activity (NP(o)) and on channel expression in membranes of isolated human myometrial smooth muscle cells. NP(o) in inside-out patches was higher in pregnant myometria (PM) compared with nonpregnant myometria (NPM), and the half-maximal activation potential was shifted by 39 mV to more negative potentials. This effect was not due to an enhanced BK(Ca) channel expression. In the presence of cAMP kinase (PKA) or cGMP kinase (PKG), NP(o) increased in patches from PM but decreased in those from NPM. Western blot analysis and use of a specific PKG inhibitor (1 microM KT-5823) verified the existence of a partially active membrane-associated PKG. Inhibition of PKA by 100 nM PKI, the inhibitory peptide of PKA, had no effect on NP(o). 8-p-Chlorophenylthio-cGMP (8-pCPT-cGMP) hyperpolarized cells from PM. This effect was abolished by iberiotoxin, a specific blocker of BK(Ca) channels. It is concluded that an endogenous, membrane-bound PKG in myometrial cells specifically enhances BK(Ca) channel activity during pregnancy and thus may contribute to uterine quiescence during pregnancy.

α5β1 Integrin Engagement Increases Large Conductance, Ca2+-activated K+ Channel Current and Ca2+ Sensitivity through c-src-mediated Channel Phosphorylation

“…that regulation occurs through a membrane-delimited pathway. This conclusion is consistent with other electrophysiological studies of the BK channel, where channel regulation by kinases has also been demonstrated in excised patches (7,8,29,(37)(38)(39)(40)(41)(42)(43). Our biochemical assays (Figs.…”

Potassium channels and uterine function

“…Enhanced activity of BKCa channels in pregnancy is often due to differential phosphorylation rather than an increase in BKCa expression levels. The membrane-bound PKG activates BKCa channels in human non-laboring myometrium thus contributing to myometrial quiescence during gestation [25]. Similarly, in rats, BKCa isoforms inhibited by PKA phosphorylation decreased throughout pregnancy whereas expression of isoforms activated by PKA peaked at mid-gestation [20].…”

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

“…Numerous functions have been attributed to BK channels, including modulation of smooth muscle tone of blood vessels and uterus (Zhou et al, 2000;, synaptic neurotransmitter release (Robitaille and Charlton, 1992) and epithelial transport (Kunzelmann and Mall, 2002). Most recently, attention has been drawn to the BK channel as a critical player in blood pressure regulation and in the neurotropic effect of ethanol (Davies et al, 2003).…”