Renal sodium channels: Regulation and single channel properties

Eaton, Douglas C.; Becchetti, Andrea; Ma, Heping; Ling, Brian N.

doi:10.1038/ki.1995.375

Cited by 67 publications

(52 citation statements)

References 66 publications

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“…␣ , ␤ , and ␥ sodium channel subunits have been identified both in the renal (11) and nasal epithelium (12) by in situ hybridization techniques. In cultured cells from both tissues, patch clamp experiments have identified channels selective for sodium and sensitive to blockade by amiloride which are thought to be assembled from ␣ , ␤ , and ␥ subunits (13,14). Therefore, mutations of ␤ or ␥ subunits seen in families with Liddle's syndrome might be expected to alter the activity of both renal and nasal sodium channels.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Baker¹,

Jeunemaı̂tre²,

Portal³

et al. 1998

J. Clin. Invest.

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In Liddle's syndrome, a rare inherited form of hypertension, epithelial sodium channel mutations appear to cause high blood pressure by increasing sodium reabsorption through sodium channels in the renal distal tubule. This increase in channel activity has not been confirmed previously by in vivo measurement. We have made transnasal potential difference measurements (effective in detection of increased sodium channel activity in cystic fibrosis) in three brothers with genetically proven Liddle's syndrome, their unaffected sister, and 40 normotensive controls. Maximum potential difference after 2 wk off treatment in the affected brothers was Ϫ 30.4 Ϯ 1.2 mV (values mean Ϯ SD, lumen-negative with respect to submucosa) and was significantly more lumen-negative than that of the control group ( Ϫ 18.6 Ϯ 6.8 mV, P ϭ 0.0228) or the unaffected sister ( Ϫ 18.25 mV, P Ͻ 0.01). The change in potential difference after topical application of 10 Ϫ 4 M amiloride was greater in the Liddle's patients, 14.0 Ϯ 2.1 mV, than in controls (7.9 Ϯ 3.9 mV, P ϭ

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Section: Discussionmentioning

confidence: 99%

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Baker¹,

Jeunemaı̂tre²,

Portal³

et al. 1998

J. Clin. Invest.

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“…A similar role for PKC in sodium channel regulation by sodium feedback and prostaglandin E2 has been described in X. laevis A6 cells that are used as a model for cortical collecting duct principal cells (Ling and Eaton, 1989;Eaton et al, 1995). A direct stimulation of PKC by phorbol esters has also been shown to inhibit amiloride-sensitive sodium transport and to activate Cl conductive pathways leading to Cl secretion across A6 epithelia (Yanase and Handler, 1986).…”

Section: Introductionmentioning

confidence: 99%

Phorbol 12-myristate 13-acetate down-regulates Na,K-ATPase independent of its protein kinase C site: decrease in basolateral cell surface area.

Beron

Forster

Béguin

et al. 1997

MBoC

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The effect of protein kinase C (PKC) stimulation on the pump current (Up) generated by the Na,K-ATPase was measured in A6 epithelia apically permeabilized with amphotericin B. Phorbol 12-myristate 13-acetate (PMA) produced a decrease in I carried by sodium pumps containing the endogenous Xenopus laevis or transfected BuJ'o marinus al subunits (-30% reduction within 25 min, maximum after 40 min) independent of the PKC phosphorylation site (T15A/S16A). In addition to this major effect of PMA, which was independent of the intracellular sodium concentration and was prevented by the PKC inhibitor bisindolylmaleimide GF 109203X (BIM), another BIM-resistant, PKC siteindependent decrease was observed when the Ip was measured at low sodium concentrations (total reduction -50% at 5 mM sodium). Using ouabain binding and cell surface biotinylation, stimulation of PKC was shown to reduce surface Na,K-ATPase by 14 to 20% within 25 min. The same treatment stimulated fluid phase endocytosis sevenfold and decreased by 16.5% the basolateral cell surface area measured by transepithelial capacitance measurements. In conclusion, PKC stimulation produces a decrease in sodium pump function which can be attributed, to a large extent, to a withdrawal of sodium pumps from the basolateral cell surface independent of their PKC site. This

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“…The channel is regulated by hormones such as aldosterone, insulin, and antidiuretic hormone that increase its activity by diverse mechanisms including increase in channel synthesis, incorporation of channels from an intracellular pool to the plasma membrane, and induction of post-translational modifications of the channel proteins (1). There are fewer known mechanisms that decrease sodium permeability in cells expressing ENaC.…”

mentioning

confidence: 99%

“…Expression of the amiloride-sensitive epithelial sodium channel (ENaC) 1 in the plasma membrane determines the sodium permeability of many epithelia involved in sodium reabsorption. The channel is regulated by hormones such as aldosterone, insulin, and antidiuretic hormone that increase its activity by diverse mechanisms including increase in channel synthesis, incorporation of channels from an intracellular pool to the plasma membrane, and induction of post-translational modifications of the channel proteins (1).…”

mentioning

confidence: 99%

The Activity of the Epithelial Sodium Channel Is Regulated by Clathrin-mediated Endocytosis

Shimkets¹,

Lifton²,

Canessa³

1997

Journal of Biological Chemistry

252

220

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Activity of the epithelial sodium channel (ENaC) is a key determinant of sodium homeostasis and blood pressure. Liddle's syndrome, an inherited form of hypertension, is caused by mutations that delete or alter PY domains in the carboxyl termini of ␤ or ␥ ENaC subunits, leading to increased channel activity. In this study we investigated the mechanism of this effect by analysis of wild-type and mutant ENaC activity in Xenopus oocytes. By inhibiting insertion of new channels into the plasma membrane with brefeldin A, we demonstrate that the half-life of the activity of channels containing Liddle's mutations is markedly prolonged compared with wildtype channels (t1 ⁄2 of 30 h in mutant versus 3.6 in wildtype, p < 0.001). We investigated the involvement of clathrin-coated pit-mediated endocytosis by co-expressing a dominant-negative dynamin mutant with wildtype ENaC in oocytes. Expression of this specific inhibitor of endocytosis leads to a large increase in the activity of wild-type channels, demonstrating that normal turnover of this channel is through the clathrincoated pit pathway. In contrast, co-expression of Liddle's mutations and dynamin mutants leads to no further increase in channel activity, consistent with one of the effects of Liddle's mutations being the loss of endocytosis of these channels. These findings demonstrate the normal mechanism of turnover of ENaC from the cell surface and demonstrate a mechanism that can account for the increased number of channels in the plasma membrane seen in Liddle's syndrome.Expression of the amiloride-sensitive epithelial sodium channel (ENaC) 1 in the plasma membrane determines the sodium permeability of many epithelia involved in sodium reabsorption. The channel is regulated by hormones such as aldosterone, insulin, and antidiuretic hormone that increase its activity by diverse mechanisms including increase in channel synthesis, incorporation of channels from an intracellular pool to the plasma membrane, and induction of post-translational modifications of the channel proteins (1). There are fewer known mechanisms that decrease sodium permeability in cells expressing ENaC. Recently, there have been several studies that implicate the carboxyl terminus of the channel subunits in processes that normally down-regulate its activity. Mutations in the human genes of the ␤ and ␥ subunits cause a form of salt-sensitive hypertension known as Liddle's syndrome (2, 3). These mutations introduce frameshifts or premature stop codons that delete the intracellular carboxyl-terminal domains of the ␤ or ␥ subunits, or they substitute residues in a prolinerich motif present in the carboxyl termini of both subunits (4, 5). Expression of ENaC channels with truncated ␤ or ␥ subunits in Xenopus oocytes induces amiloride-sensitive whole-cell currents 3-5-fold larger in magnitude than wild-type channels (6). Two mechanisms have been proposed to explain the increase in sodium permeability induced by Liddle's mutations: an increase in the number of channels expressed at the cell surface, a...

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Renal sodium channels: Regulation and single channel properties

Cited by 67 publications

References 66 publications

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Phorbol 12-myristate 13-acetate down-regulates Na,K-ATPase independent of its protein kinase C site: decrease in basolateral cell surface area.

The Activity of the Epithelial Sodium Channel Is Regulated by Clathrin-mediated Endocytosis

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