Scaffold Protein Connector Enhancer of Kinase Suppressor of Ras Isoform 3 (CNK3) Coordinates Assembly of a Multiprotein Epithelial Sodium Channel (ENaC)-regulatory Complex

Soundararajan, Rama; Ziera, Tim; Koo, Eric; Wang, Jian; Borden, Steffen A.; Pearce, David

doi:10.1074/jbc.m112.389148

Cited by 31 publications

(18 citation statements)

References 80 publications

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“…Polyclonal anti-SGK1 isoform antiserum (1:1,000; Sigma Aldrich SAB2104902; Ref. 38). Secondary antibodies were tagged with either Alexa Fluor 680 (Invitrogen) or IRDye 800 (LI-COR, Lincoln, NE).…”

Section: Quantitative Immunoblotting and Reagentsmentioning

confidence: 99%

Increasing plasma [K⁺] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Rengarajan

Lee

et al. 2014

American Journal of Physiology-Renal Physiology

121

134

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Dietary potassium loading results in rapid kaliuresis, natriuresis, and diuresis associated with reduced phosphorylation (p) of the distal tubule Na(+)-Cl(-) cotransporter (NCC). Decreased NCC-p inhibits NCC-mediated Na(+) reabsorption and shifts Na(+) downstream for reabsorption by epithelial Na(+) channels (ENaC), which can drive K(+) secretion. Whether the signal is initiated by ingesting potassium or a rise in plasma K(+) concentration ([K(+)]) is not understood. We tested the hypothesis, in male rats, that an increase in plasma [K(+)] is sufficient to reduce NCC-p and drive kaliuresis. After an overnight fast, a single 3-h 2% potassium (2%K) containing meal increased plasma [K(+)] from 4.0 ± 0.1 to 5.2 ± 0.2 mM; increased urinary K(+), Na(+), and volume excretion; decreased NCC-p by 60%; and marginally reduced cortical Na(+)-K(+)-2Cl(-) cotransporter (NKCC) phosphorylation 25% (P = 0.055). When plasma [K(+)] was increased by tail vein infusion of KCl to 5.5 ± 0.1 mM over 3 h, significant kaliuresis and natriuresis ensued, NCC-p decreased by 60%, and STE20/SPS1-related proline alanine-rich kinase (SPAK) phosphorylation was marginally reduced 35% (P = 0.052). The following were unchanged at 3 h by either the potassium-rich meal or KCl infusion: Na(+)/H(+) exchanger 3 (NHE3), NHE3-p, NKCC, ENaC subunits, and renal outer medullary K(+) channel. In summary, raising plasma [K(+)] by intravenous infusion to a level equivalent to that observed after a single potassium-rich meal triggers renal kaliuretic and natriuretic responses, independent of K(+) ingestion, likely driven by decreased NCC-p and activity sufficient to shift sodium reabsorption downstream to where Na(+) reabsorption and flow drive K(+) secretion.

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Section: Quantitative Immunoblotting and Reagentsmentioning

confidence: 99%

Increasing plasma [K⁺] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Rengarajan

Lee

et al. 2014

American Journal of Physiology-Renal Physiology

121

134

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“…Regulatory molecules within the ERC interact with the cytoplasmic domains of ENaC, which are absent in current models of the ENaC structure ( Figure 2). The formation and stability of the complex requires an aldosterone-induced chaperone (GILZ1) and a scaffold protein (CNK3) (9,10), which keep the complex together by stimulating interactions among multiple proteins ( Figure 1). It is interesting to note that CNK3, like many scaffolds involved in stabilizing membrane expression of transport proteins, has a PDZ (PSD-95/DLG-1/ZO-1) domain (1).…”

Section: Control Of Principal Cell Ion Transportmentioning

confidence: 99%

Collecting Duct Principal Cell Transport Processes and Their Regulation

Pearce

Soundararajan

Trimpert

et al. 2015

Clinical Journal of the American Society of Nephrology

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254

236

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The principal cell of the kidney collecting duct is one of the most highly regulated epithelial cell types in vertebrates. The effects of hormonal, autocrine, and paracrine factors to regulate principal cell transport processes are central to the maintenance of fluid and electrolyte balance in the face of wide variations in food and water intake. In marked contrast with the epithelial cells lining the proximal tubule, the collecting duct is electrically tight, and ion and osmotic gradients can be very high. The central role of principal cells in salt and water transport is reflected by their defining transporters-the epithelial Na 1 channel (ENaC), the renal outer medullary K 1 channel, and the aquaporin 2 (AQP2) water channel. The coordinated regulation of ENaC by aldosterone, and AQP2 by arginine vasopressin (AVP) in principal cells is essential for the control of plasma Na 1 and K 1 concentrations, extracellular fluid volume, and BP. In addition to these essential hormones, additional neuronal, physical, and chemical factors influence Na 1 , K 1 , and water homeostasis. Notably, a variety of secreted paracrine and autocrine agents such as bradykinin, ATP, endothelin, nitric oxide, and prostaglandin E 2 counterbalance and limit the natriferic effects of aldosterone and the water-retaining effects of AVP. Considerable recent progress has improved our understanding of the transporters, receptors, second messengers, and signaling events that mediate principal cell responses to changing environments in health and disease. This review primarily addresses the structure and function of the key transporters and the complex interplay of regulatory factors that modulate principal cell ion and water transport.

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“…In this context, aldosterone binds in the cytosol either to its high-affinity receptor, the mineralocorticoid receptor (MR), and/or the low-affinity receptor, the glucocorticoid receptor (GR) (2), which then translocate into the nucleus and promote a transcriptional/translational program involving aldosterone-induced and -repressed proteins. During the past 15 years, considerable progress has been made in the characterization of these cellular events, and numerous aldosteroneinduced proteins have been identified, including serum-and glucocorticoid-dependent kinase 1 (SGK1) (10,33), glucocorticoid-induced leucine zipper protein (GILZ) (40), the adaptor protein 14-3-3␤ (26), scaffold protein connector enhancer of kinase suppressor of RAS isoform 3 (CNK3) (49), or the deubiquitylating enzyme USP2-45 (14). Importantly, evidence has been provided that these proteins form a complex which may regulate ENaC function via posttranslational modifications including ubiquitylation (i.e., the posttranslational modification of target proteins with ubiquitin) (11,26,48).…”

mentioning

confidence: 99%

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

Pouly

Debonneville

Ruffieux-Daidié

et al. 2013

American Journal of Physiology-Renal Physiology

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Scaffold Protein Connector Enhancer of Kinase Suppressor of Ras Isoform 3 (CNK3) Coordinates Assembly of a Multiprotein Epithelial Sodium Channel (ENaC)-regulatory Complex

Cited by 31 publications

References 80 publications

Increasing plasma [K⁺] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Increasing plasma [K⁺] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Collecting Duct Principal Cell Transport Processes and Their Regulation

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

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Scaffold Protein Connector Enhancer of Kinase Suppressor of Ras Isoform 3 (CNK3) Coordinates Assembly of a Multiprotein Epithelial Sodium Channel (ENaC)-regulatory Complex

Cited by 31 publications

References 80 publications

Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Collecting Duct Principal Cell Transport Processes and Their Regulation

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

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Product

Resources

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Increasing plasma [K⁺] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Increasing plasma [K⁺] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis