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Regulation of renal epithelial sodium channels

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Abstract

The high selectivity, low conductance, amiloride-blockable, sodium channel of the mammalian distal nephron (i.e. cortical collecting tubule) is the site of discretionary regulation which allows maintainance of total body sodium balance. In order to understand the physiological events that participate in this regulation, we have used the patch-clamp technique which allows us to measure individual Na+ channel currents and permits access to the cytosolic side of the channel-protein as well as its associated regulatory components. Most of our experiments have utilized the A6 amphibian renal cell line, which when grown on permeable supports is an excellent model for the mammalian distal nephron. Different mechanisms have been examined: (1) regulation by hormonal factors such as Anti-Diuretic Hormone (ADH) and aldosterone, (2) regulation by G-proteins, (3) modulation by protein kinase C (PK-C), and (4) modulation by products of arachidonic acid metabolism. Consistent with noise analysis of tight epithelial tissues, ADH treatment increased the number of active channels in apical membrane patches of A6 cells, without any apparent change in the open probability (Po) of the individual channels. Agents that increased intracellular cAMP mimicked the effects of ADH. In contrast, aldosterone was found to act through a dramatic increase in Po rather than through changes in channel density. Inhibition of methylation by deazaadenosine antagonizes the stimulatory effect of aldosterone. In excised inside-out patches GTPγS inhibits channel activity, whereas GDPβS or pertussis toxin stimulates activity suggesting regulatory control by G-proteins. PK-C has been shown to contribute to ‘feed-back inhibition’ of apical Na+ conductance in tight epithelia. Raising luminal bath sodium and therefore intracellular Na+ inhibits sodium channel activity, an effect that is prevented by PK-C inhibitors and mimicked by PK-C agonists. Cyclooxygenase metabolites of arachidonic acid have an inhibitory effect on channel activity. Finally, a possible role for tyrosine kinase as well as membrane cytoskeleton in the regulation of sodium channel function is also suggested.

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Abbreviations

ADH:

Anti Diuretic Hormone

AVP:

Arginine Vasopressin

dBcAMP:

diButyryl-cyclic Adenosine Mono Phosphate

NMDG:

N-methyl-D-glucamine

PK-A:

Protein Kinase A

PK-C:

Protein kinase C

GTP:

Guanosine 5′-Triphosphate

GDPβS:

Guanosine 5′-O-(2-thiodiphosphate)

GTPγS:

Guanosine 5′-O-(3-thiotri-phosphate)

G-protein:

Trimeric Guanosine Dependent Protein

Gαi−3 :

α subunit of the Gi−3 type G- protein

CCT:

Cortical Collecting Tubule

PTX:

Pertussis Toxin

IMCD:

Inner Medulary Collecting Duct

cAMP:

Adenosine 3′:5′-cyclic Monophosphate

cGMP:

Guanosine 3′:5′-cyclic Monophosphate

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Author notes

  1. Pascal Duchatelle & Akito Ohara

    Present address: Department of Biology, Shiga University of Medical Science, 520-21, Seta Tsukinowa-cho, Ohtsu, Shiga, Japan

  2. Brian N. Ling

    Present address: Department of Medicine, Emory University School of Medicine and Veterans Administration Center, 30322, Atlanta, GA, USA

  3. Alexandra E. Kemendy

    Present address: Department of Physiology, Dartmouth Medical School, 03756, Hanover, NH, USA

Authors and Affiliations

  1. Department of Physiology, Emory University School of Medicine, 30322, Atlanta, Georgia, USA

    Pascal Duchatelle, Akito Ohara, Brian N. Ling, Alexandra E. Kemendy, Kenneth E. Kokko, Paul S. Matsumoto & Douglas C. Eaton

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  1. Pascal Duchatelle
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  2. Akito Ohara
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  3. Brian N. Ling
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  7. Douglas C. Eaton
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Duchatelle, P., Ohara, A., Ling, B.N. et al. Regulation of renal epithelial sodium channels. Mol Cell Biochem 114, 27–34 (1992). https://doi.org/10.1007/BF00240294

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