δ ENaC: a novel divergent amiloride-inhibitable sodium channel

Abstract

The fourth subunit of the epithelial sodium channel, termed delta subunit (δ ENaC), was cloned in human and monkey. Increasing evidence shows that this unique subunit and its splice variants exhibit biophysical and pharmacological properties that are divergent from those of α ENaC channels. The widespread distribution of epithelial sodium channels in both epithelial and nonepithelial tissues implies a range of physiological functions. The altered expression of SCNN1D is associated with numerous pathological conditions. Genetic studies link SCNN1D deficiency with rare genetic diseases with developmental and functional disorders in the brain, heart, and respiratory systems. Here, we review the progress of research on δ ENaC in genomics, biophysics, proteomics, physiology, pharmacology, and clinical medicine.

Fig. 1.

Phylogenetic and genomic analysis of SCNN1D. A: phylogenetic tree of SCNN1D across species. Software TreeView version 1.6.6 was used to construct phylogenetic tree. B: comparison of SCNN1D-bearing chromosome in human with murine chromosomes only containing adjacent genes.

Fig. 2.

Gene expression profile of SCNN1A, SCNN1B, SCNN1G, and SCNN1D. Expression levels are computed from the “GeneAtlas U133A, gcmas” dataset, an atlas of tissue expression (GeneAtlas) on an Affymetrix U133A array, using the gcrma algorithm to process the data. The y-axes on these graphs represent normalized, background-subtracted, and summarized (probes to probeset) intensity of each probe set: 1 kidney, 2 tonsil, 3 lymph node, 4 thymus, 5 bone marrow, 6 adrenal gland, 7 adrenal cortex, 8 olfactory bulb, 9 trachea, 10 salivary gland, 11 pituitary, 12 fetal liver, 13 fetal lung, 14 fetal thyroid, 15 uterus, 16 adipocyte, 17 pancreatic islet, 18 pancreas, 19 testis seminiferous tubule, 20 testis Leydig cell, 21 testis interstitial, 22 testis germ cell, 23 testis, 24 colorectal adenocarcinoma, 25 bronchial epithelial cells, 26 smooth muscle, 27 cardiac myocytes, 28 leukemia lymphoblastic (MOLT-4), 29 leukemia chronic myelogenous K-562, 30 lymphoma Burkitts (Daudi), 31 leukemia promyelocytic HL-60, 32 leukemia Burkitts (Raji), 33 thyroid, 34 prostate, 35 lung, 36 placenta, 37 CD71+ early erythroid, 38 small intestine, 39 colon, 40 liver, 41 heart, 42 uterus corpus, 43 appendix, 44 ovary, 45 dorsal root ganglion, 46 ciliary ganglion, 47 atrioventricular node, 48 skin, 49 trigeminal ganglion, 50 superior cervical ganglion, 51 tongue, 52 skeletal muscle, 53 retina, 54 pineal night, 55 pineal day, 56 whole brain, 57 amygdala, 58 prefrontal cortex, 59 spinal cord, 60 hypothalamus, 61 fetal brain, 62 thalamus, 63 caudate nucleus, 64 parietal lobe, 65 medulla oblongata, 66 cingulate cortex, 67 occipital lobe, 68 temporal lobe, 69 subthalamic nucleus, 70 pons, 71 globus pallidus, 72 cerebellum, 73 cerebellum peduncles, 74 CD34+, 75 CD105+ endothelial, 76 721 B lymphoblasts, 77 CD19+ B cells (neg._sel.), 78 BDCA4+ dendritic cells, 79 CD8+ T cells, 80 CD4+ T cells, 81 CD56+ NK cells, 82 CD33+ myeloid, 83 CD14+ monocytes, 84 whole blood. The bottom x-axes show the median (M) and the fold median level, as indicated by purple lines, and the top x-axes show the relative expression level with light gray lines; 176 samples for 84 types of tissues were statistically analyzed. Data are adapted from BioGPS with permission (www.BioGPS.org).

Fig. 3.

Translated proteins of SCNN1D. A: alignment of the amino acid sequences of amino-terminal tails; δ1 (CAI23262.1) and δ2 (CAI23261.1) are highlighted. M1, first transmembrane domain. B: polymorphic tree of SCNN1D proteins. The predicted translations of δ ENaC proteins are aligned with the NCBI database IDs. The total numbers of amino acids are indicated in parentheses; δ1 and δ2 proteins are highlighted.