KCa3.1 in Epithelia

Devor, Daniel C.; Thibodeau, Patrick H.; Hamilton, Kirk L.

doi:10.1007/978-3-030-55454-5_22

Cited by 2 publications

(3 citation statements)

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“…We have reported that the anterograde trafficking of KCa3.1 is dependent upon Rab-1, Rab-8, but not dependent upon transferrin- nor RME-1 (Receptor-mediated endocytosis 1) -positive recycling endosomes, nor AP-1 adaptor protein µ1B, although dependent upon the cytoskeleton and myosin-Vc ( Bertuccio et al, 2014 ; Farquhar et al, 2017 ). The above experiments have provided a mechanistic understanding of the anterograde trafficking of KCa3.1 from the ER to the BLM (further reviewed in Devor et al, 2020 ). Nonetheless, the molecular mechanism responsible for the incorporation of KCa3.1-containing vesicles into the BLM is still undetermined.…”

Section: Discussionmentioning

confidence: 99%

“…KCa3.1 (Syn, IK1, SK4) is an intermediate-conductance Ca 2+ -activated K + channel that plays crucial roles in maintaining the electrochemical driving force for Ca 2+ -mediated transepithelial Cl − secretion across polarized epithelia ( Flores et al, 2007 ; Balut et al, 2012 ; Devor et al, 2016 ; 2020 ). KCa3.1 has been well established as a channel that resides in the BLM of epithelial cells ( Devor et al, 1996 ; 1999 ; Rufo et al, 1996 ; Hamilton et al, 1999 ; Hamilton and Kiessling 2006 ), and non-epithelial tissues ( Neylon et al, 1994 , 2004 ; Rapetti-Mauss et al, 2015 ; Turner et al, 2015 ; Storck et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…KCa3.1 is critical in a wide range of physiological functions in both epithelia and non-epithelial tissues. With such a wide distribution, KCa3.1 has been touted as a potential target in a range of diseases ( Devor et al, 1996 ; Damkjaer et al, 2012 ; Bradding and Wulff, 2009 ; Köhler et al, 2010 ; Wulff and Köhler, 2013 ; Brown et al, 2020 ; Devor et al, 2020 ). Indeed, altered numbers of KCa3.1 channels expressed at the cell plasma membrane results in pathophysiological conditions such as ulcerative colitis (UC) and polycystic kidney disease (PKD).…”

Section: Introductionmentioning

confidence: 99%

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Role of SNARE Proteins in the Insertion of KCa3.1 in the Plasma Membrane of a Polarized Epithelium

et al. 2022

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Targeting proteins to a specific membrane is crucial for proper epithelial cell function. KCa3.1, a calcium-activated, intermediate-conductance potassium channel, is targeted to the basolateral membrane (BLM) in epithelial cells. Surprisingly, the mechanism of KCa3.1 membrane targeting is poorly understood. We previously reported that targeting of KCa3.1 to the BLM of epithelial cells is Myosin-Vc-, Rab1-and Rab8-dependent. Here, we examine the role of the SNARE proteins VAMP3, SNAP-23 and syntaxin 4 (STX-4) in the targeting of KCa3.1 to the BLM of Fischer rat thyroid (FRT) epithelial cells. We carried out immunoblot, siRNA and Ussing chamber experiments on FRT cells, stably expressing KCa3.1-BLAP/Bir-A-KDEL, grown as high-resistance monolayers. siRNA-mediated knockdown of VAMP3 reduced BLM expression of KCa3.1 by 57 ± 5% (p ≤ 0.05, n = 5). Measurements of BLM-localized KCa3.1 currents, in Ussing chambers, demonstrated knockdown of VAMP3 reduced KCa3.1 current by 70 ± 4% (p ≤ 0.05, n = 5). Similarly, siRNA knockdown of SNAP-23 reduced the expression of KCa3.1 at the BLM by 56 ± 7% (p ≤ 0.01, n = 6) and reduced KCa3.1 current by 80 ± 11% (p ≤ 0.05, n = 6). Also, knockdown of STX-4 lowered the BLM expression of KCa3.1 by 54 ± 6% (p ≤ 0.05, n = 5) and reduced KCa3.1 current by 78 ± 11% (p ≤ 0.05, n = 5). Finally, co-immunoprecipitation experiments demonstrated associations between KCa3.1, VAMP3, SNAP-23 and STX-4. These data indicate that VAMP3, SNAP-23 and STX-4 are critical for the targeting KCa3.1 to BLM of polarized epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of SNARE Proteins in the Insertion of KCa3.1 in the Plasma Membrane of a Polarized Epithelium

et al. 2022

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The exocyst complex is required for the trafficking and delivery of KCa3.1 to the basolateral membrane of polarized epithelia

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Farquhar

Eckhoff-Björngard

et al. 2023

American Journal of Physiology-Cell Physiology

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Control of the movement of ions and water across epithelia is essential for homeostasis. Changing the number or activity of ion channels at the plasma membrane is a significant regulator of epithelial transport. In polarized epithelia, the intermediate-conductance calcium-activated potassium channel, KCa3.1 is delivered to the basolateral membrane where it generates and maintains the electrochemical gradients required for epithelial transport. The mechanisms that control the delivery of KCa3.1 to the basolateral membrane are still emerging. Herein we investigated the role of the highly conserved tethering complex exocyst. In epithelia, exocyst is involved in the tethering of post-Golgi secretory vesicles with the basolateral membrane, which is required before membrane fusion. In our Fisher rat thyroid cell line that stably expresses KCa3.1, siRNA knockdown of either of the exocyst subunits Sec3, Sec6, or Sec8 significantly decreased KCa3.1-specific current. Additionally, knockdown of exocyst complex subunits significantly reduced the basolateral membrane protein level of KCa3.1. Finally, co-immunoprecipitation experiments, suggest associations between Sec6 and KCa3.1, but not between Sec8 and KCa3.1. Collectively, based on these data and our previous studies, we suggest that components of exocyst complex are crucially important in the tethering of KCa3.1 to the basolateral membrane. After which, SNARE proteins aid in the insertion of KCa3.1-containing vesicles into the basolateral membrane of polarized epithelia.

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KCa3.1 in Epithelia

Cited by 2 publications

References 283 publications

Role of SNARE Proteins in the Insertion of KCa3.1 in the Plasma Membrane of a Polarized Epithelium

Role of SNARE Proteins in the Insertion of KCa3.1 in the Plasma Membrane of a Polarized Epithelium

The exocyst complex is required for the trafficking and delivery of KCa3.1 to the basolateral membrane of polarized epithelia

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