KCNQ1 loss-of-function mutation impairs gastric acid secretion in mice

Pan, Qin; Ma, Jiguang; Qi-xin, Zhou; Li, Jun; Yongqing, Tang; Liu, Yi; Yang, Yi‐Qing; Xiao, Junjie; Peng, Luying; Li, Pengjuan; Liang, Dandan; Zhang, Hong; Chen, Yihan

doi:10.1007/s11033-009-9511-9

Cited by 17 publications

(14 citation statements)

References 19 publications

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“…KCNQ1 channel blockers inhibit acid secretion [14,16,17], and both KCNQ1-deficient and KCNE2-deficient mice exhibit loss of acid secretion [18][19][20][21], suggesting an essential role of KCNQ1 in acid secretion.…”

Section: Introductionmentioning

confidence: 99%

Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse

et al. 2010

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“…Kv7.1 is also expressed in other epithelial tissues, including colon, where the channel is important for cAMP-induced chloride secretion (1,11,38), the kidney where the channel is involved in salt and water transport (38), and in gastric parietal cells in the stomach where it regulates gastric acid secretion (11,26,32).…”

mentioning

confidence: 99%

Protein kinase A stimulates Kv7.1 surface expression by regulating Nedd4-2-dependent endocytic trafficking

Andersen

Hefting

Steffensen

et al. 2015

American Journal of Physiology-Cell Physiology

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The potassium channel Kv7.1 plays critical physiological roles in both heart and epithelial tissues. In heart, Kv7.1 and the accessory subunit KCNE1 forms the slowly activating delayed-rectifier potassium current current, which is enhanced by protein kinase A (PKA)-mediated phosphorylation. The observed current increase requires both phosphorylation of Kv7.1 and the presence of KCNE1. However, PKA also stimulates Kv7.1 currents in epithelial tissues, such as colon, where the channel does not coassemble with KCNE1. Here, we demonstrate that PKA activity significantly impacts the subcellular localization of Kv7.1 in Madin-Darby canine kidney cells. While PKA inhibition reduced the fraction of channels at the cell surface, PKA activation increased it. We show that PKA inhibition led to intracellular accumulation of Kv7.1 in late endosomes/lysosomes. By mass spectroscopy we identified eight phosphorylated residues on Kv7.1, however, none appeared to play a role in the observed response. Instead, we found that PKA acted by regulating endocytic trafficking involving the ubiquitin ligase Nedd4-2. We show that a Nedd4-2-resistant Kv7.1-mutant displayed significantly reduced intracellular accumulation upon PKA inhibition. Similar effects were observed upon siRNA knockdown of Nedd4-2. However, although Nedd4-2 is known to regulate Kv7.1 by ubiquitylation, biochemical analyses demonstrated that PKA did not influence the amount of Nedd4-2 bound to Kv7.1 or the ubiquitylation level of the channel. This suggests that PKA influences Nedd4-2-dependent Kv7.1 transport though a different molecular mechanism. In summary, we identify a novel mechanism whereby PKA can increase Kv7.1 current levels, namely by regulating Nedd4-2-dependent Kv7.1 transport.

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“…But they suffered from even higher level of urinary potassium (J343 vs C57BL/6J: 147. In terms of the possible mechanism, KCNQ1 A340E may alter electrolyte metabolism, and finally electrolyte homeostasis, at its transcriptional, translational, and functional levels (Pan et al, 2010;Choveau and Shapiro, 2012). Both KCNQ1 mRNA and protein levels were therefore tested in the stomach, intestine, cecum, colon-rectum, and kidney of the J343 and C57BL/6J mice, revealing no detectable difference between the two mouse lines.…”

Section: Discussionmentioning

confidence: 99%

“…), and is associated with various physiological functions (cardiocyte repolarization, gastric acidification, electrolyte excretion/reabsorption, etc.) (Schroeder et al, 2000;Vallon et al, 2001Vallon et al, , 2005Warth et al, 2002;Lang et al, 2007;Yang et al, 2007;Das et al, 2009;Pan et al, 2010;Amin et al, 2012;Sung et al, 2014). In the mouse kidney, KCNQ1 mRNA is expressed in the PT, DCT, CNT, CD, and glomeruli (Wang, 2004;Zheng et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In brief, the heterologous assembly of KCNQ1/ KCNE2 dominates the potassium channels in parietal cells of the stomach and then determines the secretion of gastric acid by H + /K + -ATPase-dependent K + recycling (Dedek and Waldegger, 2001;Pan et al, 2010). Coupling of KCNQ1 and KCNE1 (another member of the KCNE family) in the mouse pancreatic acini leads to a voltage-dependent K + current necessary for electrolyte and enzyme secretion (Warth et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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KCNQ1 A340E impairs electrolyte homeostasis independently of the renin-angiotensin-aldosterone system in mice

et al. 2016

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ABSTRACT. KCNQ1 (KvLQT1) is the pore-forming a-subunit of the potassium channel. To uncover its role in electrolyte metabolism, we investigated the effects of KCNQ1 A340E, a loss-of-function mutant, on J343 mice. Compared with the normal controls (C57BL/6J mice) bearing the wild-type KCNQ1 gene, J343 mice bearing KCNQ1 A340E demonstrated a much higher 24-h intake of electrolytes (potassium, sodium, and chloride). However, they suffered from significant electrolyte loss through both the feces and urine during a period of 24 h. Unbalance in electrolyte metabolism disrupted the electrolyte homeostasis in the J343 mice, which was characterized by the comparatively lower level of serum potassium (J343 vs C57BL/6J: 12.06 ± 1.47 vs 14.44 ± 3.58 mM, P = 0.01) and higher levels of serum sodium (J343 vs C57BL/6J: 148.05 ± 4.47 vs 115.15 ± 17.25 mM, P = 4.20 x 10 -4 ) and chloride (J343 vs C57BL/6J: 118.0 ± 4.47 vs 85.21 ± 11.90 mM, P = 2.47 x 10 -5 ). Between the J343 and C57BL/6J mice, there was no statistically significant difference in KCNQ1 expression in the gastrointestinal tract and kidney. Normal concentrations of plasma renin, angiotensin I, and aldosterone were also detected in both lines of mice. KCNQ1, therefore, is suggested to play a central role in electrolyte metabolism. KCNQ1 A340E, with the loss-of-function phenotype, may dysregulate electrolyte homeostasis in mice independently of the activity of the renin-angiotensin-aldosterone system.

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KCNQ1 loss-of-function mutation impairs gastric acid secretion in mice

Cited by 17 publications

References 19 publications

Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse

Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse

Protein kinase A stimulates Kv7.1 surface expression by regulating Nedd4-2-dependent endocytic trafficking

KCNQ1 A340E impairs electrolyte homeostasis independently of the renin-angiotensin-aldosterone system in mice

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