NFATc3 regulates BK channel function in murine urinary bladder smooth muscle
J J Layne1, M E Werner, D C Hill-Eubanks
1Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
Abstract:
The nuclear factor of activated T-cells (NFAT) is a Ca(2+)-dependent transcription factor that has been reported to regulate the expression of smooth muscle contractile proteins and ion channels. Here we report that large conductance Ca(2+)-sensitive potassium (BK) channels and voltage-gated K(+) (K(V)) channels may be regulatory targets of NFATc3 in urinary bladder smooth muscle (UBSM). UBSM myocytes from NFATc3-null mice displayed a reduction in iberiotoxin (IBTX)-sensitive BK currents, a decrease in mRNA for the pore-forming alpha-subunit of the BK channel, and a reduction in BK channel density compared with myocytes from wild-type mice. Tetraethylammonium chloride-sensitive K(V) currents were elevated in UBSM myocytes from NFATc3-null mice, as was mRNA for the Shab family member K(V)2.1. Despite K(V) current upregulation, bladder strips from NFATc3-null mice displayed an elevated contractile response to electrical field stimulation relative to strips from wild-type mice, but this difference was abrogated in the presence of the BK channel blocker IBTX. These results support a role for the transcription factor NFATc3 in regulating UBSM contractility, primarily through an NFATc3-dependent increase in BK channel activity.
Insights
Nuclear factor of activated T-cells c3 (NFATc3) regulates urinary bladder smooth muscle (UBSM) contractility. NFATc3 influences large conductance Ca(2+)-sensitive potassium (BK) channels, impacting UBSM function.
Area of Science:
- Physiology
- Molecular Biology
- Urology
Background:
- Nuclear factor of activated T-cells (NFAT) is a calcium-dependent transcription factor involved in smooth muscle regulation.
- Specific NFAT isoforms and their roles in urinary bladder smooth muscle (UBSM) contractility are not fully understood.
Purpose of the Study:
- To investigate the role of NFATc3 in regulating ion channels and contractility in UBSM.
- To determine if large conductance Ca(2+)-sensitive potassium (BK) channels and voltage-gated K(+) (K(V)) channels are targets of NFATc3 in UBSM.
Main Methods:
- Utilized NFATc3-null mice and wild-type littermates.
- Performed electrophysiological recordings (e.g., IBTX-sensitive BK currents, tetraethylammonium chloride-sensitive K(V) currents) on UBSM myocytes.
- Quantified mRNA levels for BK channel alpha-subunit and K(V)2.1.
- Assessed contractile responses of bladder strips using electrical field stimulation.
Main Results:
- NFATc3-null UBSM myocytes showed reduced BK currents and BK channel density, with decreased BK channel alpha-subunit mRNA.
- Elevated K(V) currents and K(V)2.1 mRNA were observed in NFATc3-null UBSM myocytes.
- Bladder strips from NFATc3-null mice exhibited enhanced contractility, which was normalized by BK channel blockade.
Conclusions:
- NFATc3 plays a crucial role in regulating UBSM contractility.
- NFATc3 primarily enhances UBSM contractility by increasing BK channel activity.
- NFATc3 influences both BK and K(V) channel expression and function in UBSM.
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