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NFATc3 regulates BK channel function in murine urinary bladder smooth muscle.

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.

SUBMITTER: Layne JJ

PROVIDER: S-EPMC2544435 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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NFATc3 regulates BK channel function in murine urinary bladder smooth muscle.

Layne J J JJ Werner M E ME Hill-Eubanks D C DC Nelson M T MT

American journal of physiology. Cell physiology 20080625 3

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 decr ...[more]

PMID: 18579799

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Project description:Aims:Type 2 diabetes (T2D) is strongly associated with cardiovascular morbidity and mortality in patients. Vascular large conductance Ca2+-activated potassium (BK) channels, composed of four pore-forming ? subunits (BK-?), and four regulatory ?1 subunits (BK-?1), are densely expressed in coronary arterial smooth muscle cells (SMCs) and play an important role in regulating vascular tone and myocardial perfusion. However, the role of BK channels in coronary microvascular dysfunction of human subjects with diabetes is unclear. In this study, we examined BK channel function and protein expression, and BK channel-mediated vasodilation in freshly isolated coronary arterioles from T2D patients. Methods and results:Atrial tissues were obtained from 16 patients with T2D and 25 matched non-diabetic subjects during cardiopulmonary bypass procedure. Microvessel videomicroscopy and immunoblot analysis were performed in freshly dissected coronary arterioles and inside-out single BK channel currents was recorded in enzymatically isolated coronary arteriolar SMCs. We found that BK channel sensitivity to physiological Ca2+ concentration and voltage was downregulated in the coronary arteriolar SMCs of diabetic patients, compared with non-diabetic controls. BK channel kinetics analysis revealed that there was significant shortening of the mean open time and prolongation of the mean closed time in diabetic patients, resulting in a remarkable reduction of the channel open probability. Functional studies showed that BK channel activation by dehydrosoyasaponin-1 was diminished and that BK channel-mediated vasodilation in response to shear stress was impaired in diabetic coronary arterioles. Immunoblot experiments confirmed that the protein expressions of BK-? and BK-?1 subunits were significantly downregulated, but the ratio of BK-?/BK-?1 was unchanged in the coronary arterioles of T2D patients. Conclusions:Our results demonstrated for the first time that BK channel function and BK channel-mediated vasodilation were abnormal in the coronary microvasculature of diabetic patients, due to decreased protein expression and altered intrinsic properties of BK channels.

Dataset Information

NFATc3 regulates BK channel function in murine urinary bladder smooth muscle.

Publications

NFATc3 regulates BK channel function in murine urinary bladder smooth muscle.

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