EGF and HB-EGF modulate inward potassium current in human bladder urothelial cells from normal and interstitial cystitis patients

Sun, Yue; Chen, Mingkui; Lowentritt, Benjamin; Zijl, P. Sean Van; Koch, Kristopher R.; Keay, Susan; Simard, J. Marc; Chai, Toby C.

doi:10.1152/ajpcell.00209.2006

Cited by 27 publications

(28 citation statements)

References 36 publications

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“…However, co-application of genistein with bpV(Phen) in differentiated myoblasts expressing Kir2.1 channels reduces the bpV(Phen)-induced Kir2.1 inhibition. Recently, it has been shown that a genistein pretreatment blocks the EGF-induced inhibition of Kir2.1 channels in urothelial cells (Sun et al, 2007). This observation supports the hypothesis that Kir2.1 channels activity can be directly modulated by a tyrosine phosphorylation.…”

Section: Kir21 Current Is Directly Modulated By the Tyrosine 242 Phosupporting

confidence: 72%

Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242

et al. 2008

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Myoblast differentiation is essential to skeletal muscle formation and repair. The earliest detectable event leading to human myoblast differentiation is an upregulation of Kir2.1 channel activity, which causes a negative shift (hyperpolarization) of the resting potential of myoblasts. After exploring various mechanisms, we found that this upregulation of Kir2.1 was due to dephosphorylation of the channel itself. Application of genistein, a tyrosine kinase inhibitor, increased Kir2.1 activity and triggered the differentiation process, whereas application of bpV(Phen), a tyrosine phosphatase inhibitor, had the opposite effects. We could show that increased Kir2.1 activity requires dephosphorylation of tyrosine 242; replacing this tyrosine in Kir2.1 by a phenylalanine abolished inhibition by bpV(Phen). Finally, we found that the level of tyrosine phosphorylation in endogenous Kir2.1 channels is considerably reduced during differentiation when compared with proliferation. We propose that Kir2.1 channels are already present at the membrane of proliferating, undifferentiated human myoblasts but in a silent state, and that Kir2.1 tyrosine 242 dephosphorylation triggers differentiation

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Section: Kir21 Current Is Directly Modulated By the Tyrosine 242 Phosupporting

confidence: 72%

Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242

et al. 2008

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“…More recently, Sun and coworkers (33) discovered a channel in cultured human bladder epithelial cells with a strong inward-rectifying potassium current and conductance characteristics of the K ir 2.1 potassium channel. They also corroborated the presence of both K ir 2.1 and a large-conductance calcium-activated potassium channel (BK, or Maxi-K) presence in cultured human urothelial cells by RT-PCR and Western blot analysis (33). The cellular location of these channels was not reported.…”

supporting

confidence: 52%

“…Although the mechanism(s) of potassium reabsorption may, in part, be secondary to passive diffusion and or leak across the apical cell membrane or through tight junctions, in recent electrophysiological studies, Sun and coworkers (33) showed a strongly rectifying potassium current with conductive characteristics of the K ir 2.1 channel as well as the Maxi-K channel in normal cultured human bladder cells (33), and, in Ussing chamber experiments with rabbit bladder, Wang et al (35) demonstrated that increased mucosal hydraulic pressure led to increased sodium reabsorption (probably through ENaC) as well as potassium secretion, likely through a stretch-activated nonselective cation channel. Although none of these channels had the characteristics of ROMK channels, these findings support the hypothesis that multiple potassium channels and transporters are present in urothelia as is the case for renal epithelia.…”

Section: Discussionmentioning

confidence: 99%

The ROMK potassium channel is present in mammalian urinary tract epithelia and muscle

Spector¹,

Yang²,

Klopouh³

et al. 2008

American Journal of Physiology-Renal Physiology

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There is increasing evidence that mammalian urinary tract epithelial cells utilize membrane channels and transporters to transport solutes across their apical (luminal) and basalateral membranes to modify solute concentrations in both cell and urine. This study investigates the expression, localization, and regulation of the ROMK (Kir 1.1) potassium channels in rat and dog ureter and bladder tissues. Immunoblots of homogenates of whole ureter, whole bladder, bladder epithelial cells, and bladder smooth muscle tissues in both rat and dog identified ϳ45-to 50-kDa bands characteristic of ROMK in all tissues. RT-PCR identified ROMK mRNA in these same tissues in both animal species. ROMK protein localized by immunocytochemistry was strongly expressed in the apical membranes of the large umbrella cells lining the bladder lumen and to a lesser extent in the cytoplasm of epithelial cells and smooth muscle cells in the rat bladder. ROMK protein and mRNA were also discovered in cardiac, striated, and smooth muscle in diverse organs. There was no difference in immunoblot expression of ROMK abundance in bladder homogenates (whole bladder, epithelial cell, or muscle cell) or ureteral homogenates between groups of rats fed high-or low-potassium diets. Although the functional role of ROMK in urinary tract epithelia and smooth muscle is unknown, ROMK may participate in the regulation of epithelial and smooth muscle cell volume and osmolality, in the dissipation of potassium leaked or diffused from urine across the epithelial cell apical membranes or tight junctions, and in net or bidirectional potassium transport across urinary tract epithelia. epithelial sodium channel; calponin MAMMALIAN URINARY TRACT EPITHELIA (urothelia) has long been held to serve solely as a storage conduct for urine made by the kidney and, in particular, to prevent modification of urine by inhibiting net flux of water and solutes across the epithelial cell luminal membrane (7). The barrier(s) preventing transepithelial flux of urine constituents have been shown to include: the lumenal membrane (containing unique uroplakin proteins) of the large ("umbrella") cells lining the urinary tract lumen (12), tight junctions adjoining the umbrella cells, and a glycosaminoglycans layer overlying and adjacent to the lumenal membrane (13, reviewed in Ref. 17). Evidence for the effectiveness of these barriers, which have been thought to be passive in nature and not to utilize or require membrane transporters, comes from Ussing chamber studies documenting very low urothelial permeability to water, ions, and nonelectrolytes and very high transepithelial cell resistance in stretched bladders and apical membrane endosomes obtained from rabbits under basal conditions (2, 24).However, although the permeabilities of urothelia for water and various urinary solutes may be low under basal conditions, urothelial permeabilities in animals subjected to dietary, physiological (e.g., water loading/water restricted), or other stress could be altered. Furthermore, urothelial cells are...

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“…In this report, the author postulates that these diseases share ''dysfunctional urinary epithelium and potassium recycling'' impairment (30). Furthermore, all these diseases have been reported to respond to phytoestrogens, such as sitosterols, quercetin, and genistein (31)(32)(33). Many phytoestrogens, like genistein, are better ligands for ER␤ than ER␣ (34,35).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

Imamov

Yakimchuk

Morani

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Interstitial cystitis/painful bladder syndrome is a disease seen mostly in women, and symptoms tend to be worse premenopausally or during ovulation. The four cardinal symptoms of interstitial cystitis/painful bladder syndrome are bladder pain, urgency, frequency, and nocturia. Estrogen has been implicated in the etiology of this disease, but the role of the two estrogen receptors (ER), ER␣ and ER␤, has not been investigated. We found that, in the bladders of WT mice, ER␤ is expressed in the basal cell layer of the urothelium. Bladders of male ER␤ ؊/؊ mice were intact and morphologically indistinguishable from those of their WT littermates. However, in female ER␤ ؊/؊ mice, there was ulceration and atrophy of bladder urothelium concomitant with infiltration of ␥␦ T cells concentrated in the areas of atrophy and shedding of urothelium. The data support the idea that activated ␥␦ T cells are causing the damage to the urothelium. The hyperactivity of T cells may be because of an imbalance between ER␣ and ER␤ signaling in female ER␤ ؊/؊ mice. Our data suggest that reduced ER␤ signaling might have a role in the pathogenesis of interstitial cystitis, and ER␤ could be a candidate for a target of medical therapy.␥␦ T cells ͉ urothelium ͉ painful bladder syndrome T he etiology of interstitial cystitis (IC) is unknown, and available treatment options are limited and mostly palliative. There is a clear role for the immune system in this disease: increased numbers of T lymphocytes, particularly ␥␦ T cells, abnormal urothelial HLA, and overexpression of HLA class II (1) in the urothelium and lamina propria in patients with IC strongly suggest a role for autoimmunity in development of IC (2). Because IC is almost exclusively a disease of young women, and symptoms tend to worsen premenopausally or during ovulation, the role of estrogen receptors (ERs) is likely to be important.The bladder is one of those tissues that were long thought to be nonestrogen-responsive on the basis of the lack of ER␣ expression. The discovery of the second ER, ER␤, provided an explanation for the effects of estrogen in several ER␣-negative tissues such as the prostate, intestine, and lung, where ER␤ serves as a modulator of terminal differentiation of epithelium (3-7). ER␤ and ER␣ knockout mice (ER␤ Ϫ/Ϫ and ER␣ Ϫ/Ϫ ) have been invaluable in analyzing and dissecting the functions of ER␤ and ER␣ (8, 9).The predominant ER in the bladder is ER␤, with very little ER␣ expression (10, 11). Reduced ER␤ expression levels have been reported in the bladders of rats with chemically induced cystitis (12). In the present study, with the use of ER␤ Ϫ/Ϫ mice, we have investigated the role of ER␤ in the bladder urothelium. We report that, in female ER␤ Ϫ/Ϫ but not in ER␣ Ϫ/Ϫ mice, there is autoimmune destruction of urothelium resembling IC. ResultsImmunohistochemical staining of WT mouse bladder sections showed that ER␤ is expressed in bladder urothelium and localized in the basal cell layer (Fig. 1). In the bladders of female ER␤ Ϫ/Ϫ mice, there were specific morphol...

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EGF and HB-EGF modulate inward potassium current in human bladder urothelial cells from normal and interstitial cystitis patients

Abstract: TC. EGF and HB-EGF modulate inward potassium current in human bladder urothelial cells from normal and interstitial cystitis patients.

Cited by 27 publications

References 36 publications

Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242

Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242

The ROMK potassium channel is present in mammalian urinary tract epithelia and muscle

Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

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