Abstract
Estrogen replacement therapies have been suggested to be beneficial in alleviating symptoms of overactive bladder. However, the precise regulatory mechanisms of estrogen in urinary bladder smooth muscle (UBSM) at the cellular level remain unknown. Large conductance voltage- and Ca2+-activated K+ (BK) channels, which are key regulators of UBSM function, are suggested to be non-genomic targets of estrogens. This study provides an electrophysiological investigation into the role of UBSM BK channels as direct targets for 17β-estradiol, the principle estrogen in human circulation. Single BK channel recordings on inside-out excised membrane patches and perforated whole cell patch-clamp were applied in combination with the BK channel selective inhibitor paxilline to elucidate the mechanism of regulation of BK channel activity by 17β-estradiol in freshly-isolated guinea pig UBSM cells. 17β-Estradiol (100 nM) significantly increased the amplitude of depolarization-induced whole cell steady-state BK currents and the frequency of spontaneous transient BK currents in freshly-isolated UBSM cells. The increase in whole cell BK currents by 17β-estradiol was eliminated upon blocking BK channels with paxilline. 17β-Estradiol (100 nM) significantly increased (~3-fold) the single BK channel open probability, indicating direct 17β-estradiol-BK channel interactions. 17β-Estradiol (100 nM) caused a significant hyperpolarization of the membrane potential of UBSM cells, and this hyperpolarization was reversed by blocking the BK channels with paxilline. 17β-Estradiol (100 nM) had no effects on L-type voltage-gated Ca2+ channel currents recorded under perforated patch-clamp conditions. This study reveals a new regulatory mechanism in the urinary bladder whereby BK channels are directly activated by 17β-estradiol to reduce UBSM cell excitability.
Highlights
The functions of the urinary bladder, which are to store and periodically release urine, are facilitated by the contraction and relaxation of urinary bladder smooth muscle (UBSM)
The current study provided the first electrophysiological evidence establishing the novel regulatory mechanism by which the BK channels are direct targets for 17β-estradiol at nanomolar concentrations in guinea pig UBSM cells
Our results demonstrate that 17β-estradiol rapidly increases: 1) the amplitude of whole cell steady-state BK currents; 2) the frequency of transient BK currents (TBKCs); 3) single BK channel NPo; and 4) hyperpolarizes the UBSM cell membrane potential; and 5) does not directly inhibit L-type CaV channel currents at nanomolar concentrations
Summary
The functions of the urinary bladder, which are to store and periodically release urine, are facilitated by the contraction and relaxation of urinary bladder smooth muscle (UBSM). Many forms of OAB have been linked directly to UBSM dysfunction [1, 2]. Systemic and vaginal estrogen therapies have been considered beneficial in alleviating symptoms of OAB in postmenopausal women [3, 4]. Epidemiological studies have linked post-menopausal estrogen deficiencies with the increased risk for OAB [3]. Despite these observations, conflicting evidence in the literature exists concerning the role of estrogen as a treatment for OAB [3]. Some studies suggest beneficial effects of estrogen replacement therapies for controlling symptoms of OAB, while other studies report the opposite [3,4,5]. There remains the need for an improved understanding of the mechanisms by which estrogens regulate UBSM function [5]
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