Dominant-Negative Regulation of Cell Surface Expression by a Pentapeptide Motif at the Extreme COOH Terminus of an Slo1 Calcium-Activated Potassium Channel Splice Variant

Chiu, Yu‐Hsin; Alvarez-Baron, Claudia P.; Kim, Eun Young; Dryer, Stuart E.

doi:10.1124/mol.109.061929

Cited by 29 publications

(31 citation statements)

References 44 publications

(70 reference statements)

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“…Auxiliary subunits can modulate ion channel surface expression and activity, but it is unclear whether the multisubunit composition of surface channels is fixed following protein synthesis or flexible and open to acute and rapid modulation (2)(3)(4). Some recombinant ion channel proteins, including large-conductance calcium (Ca 2+ )-activated potassium (BK) α subunits, can traffic to the plasma membrane in the absence of their regulatory auxiliary subunits (5)(6)(7)(8)(9). This stimulated us to investigate the hypothesis that physiological stimuli rapidly modulate surface levels of auxiliary subunits to control functional ion channel activity.…”

Section: +mentioning

confidence: 99%

Dynamic regulation of β1 subunit trafficking controls vascular contractility

Leo¹,

Bannister²,

Narayanan³

et al. 2014

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

113

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Ion channels composed of pore‐forming and auxiliary subunits control physiological functions in virtually all cell types. Whether the multi‐subunit composition of surface channels is fixed following protein synthesis or flexible and open to acute and rapid modulation to control physiological cellular functions is unclear. Arterial myocytes express large‐conductance Ca2+‐activated potassium (BK) channel α and auxiliary β1 subunits that are functionally significant modulators of arterial contractility. Here, we show that native BK α subunits are primarily (~95%) plasma membrane‐localized, whereas only a small fraction (~10%) of total β1 subunits are located at the cell surface in human and rat arterial myocytes. Immuno‐FRET microscopy demonstrated that intracellular β1 subunits are stored within Rab11A‐postive recycling endosomes. Nitric oxide (NO), acting via protein kinase G, stimulated rapid (1 min) anterograde trafficking of β1 subunit‐containing endosomes. These β1 subunits associated with surface‐resident BKα proteins, elevating Ca2+‐sensitivity and inducing activation. Data also show that rapid β1 subunit anterograde trafficking is the primary mechanism by which NO activates myocyte BK channels and induces vasodilation. In summary, we show that rapid surface trafficking of β1 subunits controls functional BK channel activity in arterial myocytes and vascular contractility. Grant Funding Source: Supported by NIH‐HL67061

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Section: +mentioning

confidence: 99%

Dynamic regulation of β1 subunit trafficking controls vascular contractility

Leo¹,

Bannister²,

Narayanan³

et al. 2014

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

113

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“…n=4; *P,0.05. membrane in the absence of its regulatory BK b subunit, 43,44 and the motif in the C-terminus of BKa also plays an important role in BKa forward trafficking. 43,44 Whether WNK1 affects the expression of BK b subunit and subsequently alters BKa forward trafficking remains to be further explored.…”

Section: Hek Bka Cells Were Transfected With a Series Of Doses Of Wnkmentioning

confidence: 99%

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Liu

Song

Shi

et al. 2015

Journal of the American Society of Nephrology

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With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca 2+ -activated K + (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the a subunit of BK (HEK-BKa cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKa channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKa protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKa expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKa expression. Similarly, pretreatment of HEK-BKa cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKa expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKa channels. Notably, mice fed a high-K + diet for 10 days had significantly higher renal protein expression levels of BKa and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K + diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel. With no lysine (WNK) kinase belongs to a family of serine/threonine kinases. Mutations of WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAІІ), characterized by hypertension, hyperkalemia, and metabolic acidosis. 1,2 The disease mutation in WNK1 or WNK4 kinase resulting in hyperkalemia suggests a role of WNK in potassium handling in renal distal nephron, which contains two major potassium channels, renal outer medullary K + channels (ROMK) and Big K (BK) channels. 3,4 WNK4 inhibits ROMK channel activity and its surface expression, whereas WNK4 disease mutant enhances its inhibitory effect on ROMK. 5 WNK1 also inhibits ROMK activity; however, a kidney-specific form of WNK1 (KS-WNK1) reverses WNK1's effect on ROMK. 6 WNK4 inhibits BK channel activity and protein expression, 7-9 whereas WNK4 disease mutant also enhances its inhibitory effect on BK activity via a ubiquitin-dependent pathway. 9 BK channel (or Maxi K) is a large conductance Ca 2+ and voltage-activated K channel. 10 BK is encoded by the gene slo1 11 and is widely distributed in many different

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“…This study also showed that chemical modifications of peptides such as the fluorophore nature can influence the intracellular fate of the delivered peptide. This work is supported by recent publications using PULSin to deliver anionic functional peptides of different lengths from 8 to 25-mer into various cellular models (Chiu et al, 2010;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Rivas et al, 2009). It also opens novel insight for functional proteomic studies and intracellular peptide-based therapy.…”

Section: Resultsmentioning

confidence: 88%

“…Interestingly, the delivered proteins retain their activity as demonstrated in functional studies (Cassinelli et al, 2006(Cassinelli et al, , 2009Chiu et al, 2010;Duerr et al, 2009;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Ohnuma et al, 2010;Okamoto et al, 2011;Rivas et al, 2009;Schafer et al, 2009;Spagnolo et al, 2010;Ying et al, 2007;Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 88%

“…In earlier studies, several groups successfully delivered proteins (Ohnuma et al, 2010;Spagnolo et al, 2010;Weill et al, 2008a;Zhang et al, 2008) including antibodies (Cassinelli et al, 2006(Cassinelli et al, , 2009Cortes et al, 2007;Duerr et al, 2009;Okamoto et al, 2011;Weill et al, 2008b;Ying et al, 2007), peptides (Chiu et al, 2010;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Rivas et al, 2009) as well as quantum-dots (Delehanty et al, 2009) using the proprietary cationic lipid-mediated delivery reagent PULSin. Interestingly, the delivered proteins retain their activity as demonstrated in functional studies (Cassinelli et al, 2006(Cassinelli et al, , 2009Chiu et al, 2010;Duerr et al, 2009;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Ohnuma et al, 2010;Okamoto et al, 2011;Rivas et al, 2009;Schafer et al, 2009;Spagnolo et al, 2010;Ying et al, 2007;Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Intracellular peptide delivery using amphiphilic lipid‐based formulations

Weiss

Neuberg

Philippot

et al. 2011

Biotech & Bioengineering

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Peptides, highly diverse by their nature, are important biochemical and pharmaceutical tools: ligands for cellular receptors, transcription factors, immunosuppressants, vaccines, etc. As the majority of their targets are intracellular, peptides need to cross the plasma membrane and gain access to the cytoplasm. However, due to their physicochemical properties, most peptides need to be entrapped by a molecular vehicle to be able to reach the cytosol compartment. In this study, we present new biological tools to enhance intracellular peptides delivery. Based on electrostatic interactions, two complementary types of amphiphilic molecules have been designed as delivery vehicles. A diverse set of fluorescently labeled peptides have successfully been delivered. This opens the avenue for the use of peptides combined to delivery vehicles as therapeutic aids.

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Dominant-Negative Regulation of Cell Surface Expression by a Pentapeptide Motif at the Extreme COOH Terminus of an Slo1 Calcium-Activated Potassium Channel Splice Variant

Cited by 29 publications

References 44 publications

Dynamic regulation of β1 subunit trafficking controls vascular contractility

Dynamic regulation of β1 subunit trafficking controls vascular contractility

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Intracellular peptide delivery using amphiphilic lipid‐based formulations

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