SCNN1D Membrane Protein Introduction

Introduction of SCNN1D

Amiloride-sensitive sodium channel subunit delta, also known as Delta-NaCH, is encoded by SCNN1D. The sequence of the SCNN1D gene is first revealed by the human genome project. SCNN1D is located in the short arm of chromosome 1 (Ensembl database code: ENSG00000162572). The Delta-NaCH shares a similar topology and 27–37% amino acid identity to the a-, b- and c-ENaC subunits. δ-ENaC is expressed as two splice isoforms with divergent NH2 termini in human and primates, but it is a pseudogene in rodents. It is able to form amiloride-sensitive, voltage-independent Na⁺ channels when expressed alone or in combination with β- and γ-subunits.

Function of SCNN1D Membrane Protein

The a-, b- and c-ENaC subunits are highly expressed in kidney, colon, and lung. In contrast, the highest transcriptional expression levels of δ-ENaC are detected in nonepithelial tissues, such as brain, pancreas, heart, testis and ovary, whilst lung, kidney, colon and several other tissues showed only low expression. Additionally, the pharmacological and biophysical properties are clearly distinct between δ- and α-ENaC-generated currents. The role of δ-ENaC is uncertain, although its biophysical properties point toward several possibilities. First, being a voltage-independent, highly selective Na⁺ channel, it could serve as a leak Na⁺ conductance, contributing to the setting of resting membrane potential. In addition, δ-ENaC currents are enhanced by a drop in extracellular pH (pHe), suggesting that it could serve as a proton sensor and be involved in the transduction of ischemic signals that occur under conditions of tissue hypoxia or inflammation.

Fig.1 Phylogenetic and genomic analysis of SCNN1D. (Ji, 2012)

Application of SCNN1D Membrane Protein in Literature

1. Agrawal P.B., et al. The epithelial sodium channel is a modifier of the long-term nonprogressive phenotype associated with F508del CFTR mutations. American Journal of Respiratory Cell and Molecular Biology. 2017, 57(6):711-720. PubMed ID: 28708422
   
   

   This article suggests that δ-ENaC may be involved in the controlling sodium reabsorption in the airways, which may provide evidence for ENaC as a therapeutic target for cystic fibrosis.

2. Schwagerus E., et al. Expression and function of the epithelial sodium channel δ-subunit in human respiratory epithelial cells in vitro. Pflugers Arch. 2015, 467(11):2257-73. PubMed ID: 25677639
   
   

   In this article, authors find that δ-ENaC expression is low in human airway epithelial cell lines (i.e. NCI-H441 and Calu-3) as well as human alveolar epithelial type I-like (ATI) cells in vitro, thus suggesting that δ-ENaC does not contribute to transepithelial sodium absorption.

3. Zhao R.Z., et al. Characterization of a novel splice variant of δ ENaC subunit in human lungs. Am J Physiol Lung Cell Mol Physiol. 2012, 302(12): L1262-72. PubMed ID: 22505667
   
   

   This article systematically characterizes a new variant of δ2 ENaC in human lung epithelial cells. Heterologous δ2βγ ENaC exhibits a number of divergent features from the δ1βγ counterpart in biophysics and pharmacology, regulation, and the lifespan of proteins. Channels comprising of this novel splice variant may contribute to the diversities of native epithelial Na⁺ channels.

4. Wesch D., et al. Differential N termini in epithelial Na+ channel δ-subunit isoforms modulate channel trafficking to the membrane. American Journal of Physiology-Cell Physiology. 2012, 302(6):C868-79. PubMed ID: 22159085
   
   

   This article reveals that δ-ENaC undergoes dynamin-independent endocytosis as opposed to αβγ-channels.

5. Chang T., et al. COMMD1 regulates the delta epithelial sodium channel (δENaC) through trafficking and ubiquitination. Biochemical and Biophysical Research Communications. 2011, 411(3):506-11. PubMed ID: 21741370
   
   

   This article suggests that COMMD1 controls dENaC cell surface population and thus regulates dENaC-mediated Na⁺ transport.

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Reference

1. Ji H L, et al. (2012). δ ENaC: a novel divergent amiloride-inhibitable sodium channel. Am J Physiol Lung Cell Mol Physiol. 303(12), L1013-26.

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