Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

OverviewThe epithelial sodium channels (ENaC) are located on the apical membrane of cells in kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat salivary glands, placenta, colon, some other organs [10, 48, 14, 23, 22]. In these epithelia, Na+ ions flow from extracellular fluid into cytoplasm via ENaC then pumped out interstitial by Na+/K+ ATPase basolateral [42]. As is one major electrolytes (ECF), osmolarity change initiated accompanied a water [7]. Thus, has central role regulating ECF volume blood pressure, primarily its function [43]. The expression subunits, hence activity, regulated renin-angiotensin-aldosterone system, factors involved electrolyte homeostasis [43, 32]. genetics hereditary systemic pseudohypoaldosteronism type-I revealed that activity dependent three subunits encoded genes [23, 12]. Within protein superfamily includes ENaC, crystal structure ASIC was determined first, revealing trimeric with large domain anchored bundle six TM helices (two helices/subunit) [3, 26]. first 3D human single-particle cryo-electron microscopy at resolution 3.7 Å [38]. A recent study improved to 3 [39]. These structures confirmed quaternary similar ASIC. assembled as hetero-trimer clockwise order α-γ-β subunit viewed top, shown previously [13]. contrast ASIC1 which can assemble functional homotrimer, be reconstituted fully only heterotrimer an αβγ or δβγ composition [29]. tract segments epithelia composed multi-ciliated cells. cells, along entire length cilia cover cell surface [16]. Cilial location greatly increases density per allows serve sensitive regulator periciliary throughout whole depth bathing CFTR (ion transporter defective cystic fibrosis) non-cilial vas deferens segment luminal covered microvilli stereocilia projections backbones actin filament bundles [48]. both channel aquaporin AQP9 localized also basal smooth muscle layers regulates lining essential for mucociliary clearance airways, transport germ fertilization, implantation, migration [37, 16, 23]. Genes PhylogenyIn genome, there four homologous (SCNN1A, SCNN1B, SCNN1D, SCNN1G) encode proteins, α-, β-, γ-, δ-ENaC may assembly [11, 34, 47, 53]. share 23-34% sequence identity <20% [23]. coding all present bony vertebrates exception ray-finned fish genomes have lost genes. mouse genome gene SCNN1D codes [18, γ-ENaC jawless (e.g., lampreys) cartilaginous fishes sharks) Examination methylation patterns 5'-flanking region SCNN1A, SCNN1G showed inverse correlation between DNA methylation, suggesting epigenetic transcriptional control [41]. Channel biogenesis, functionThe aldosterone many additional intracellular 31, 40]. Most studies indicate not coordinated [9]. However, intact subunits. Even missense mutation reduces concentration [15]. constitutively active channel, i.e., activating factor. Hence, heterologous expressing Xenopus oocytes), must maintained solution contains amiloride keep inhibited. To measure bath switched without amiloride. two states: 1) Open, 2) Closed. probability being open state called (Po). diverse array exert their effects modifying, directly indirectly, parameters: membrane; [27, 29]. Po decreased external this response self-inhibition [49, 4, 25].An important aspect regulation α γ conserved serine protease cleavage sites Cleavage proteases such furin plasmin leads activation [44, 30, 1].Diseases associated mutationsMutations any cause partial complete loss depending [12, 20]. Such loss-of-function mutations syndrome named "systemic" "multi-system" autosomal recessive type I (PHA1B) [19, 12, 55, 46]. So far, no been found causes PHA. PHA patients suffer severe salt target including kidney, glands tract. During infancy early childhood, disturbances, dehydration acidosis require recurrent hospitalizations. severity frequency salt-wasting episodes improve age [21]. PHA1B dysfunctional system [16, 6]. carboxy-terminal short consensus PY motif. Mutations motif SCNN1B Liddle syndrome, characterized early-onset hypertension [5, 50]. recognized Nedd4-2 ubiquitin ligase. reduce ubiquitylation leading accumulation membrane, consequently enhance [45].ENaC tumorsThe observation [Na+] higher cancerous compared non-cancerous led suggestion enhanced responsible increased metastasis [33]. analysis RNA sequencing data ENaC-encoding genes, clinical cervical cancer Cancer Genome Atlas negative histologic grades tumor [51]. Similarly, breast altered α-ENaC levels over-expression siRNA-mediated knockdown proliferation [54]. contrast, high SCNN1A correlated poor prognosis ovarian [35]. findings association tumorigenesis varies tissue.COVID-19The SARS-CoV-2 virions COVID-19 glycosylated S (spike) proteins. proteins bind membrane-bound angiotensin-converting enzyme 2 (ACE2) step entry virion host cell. Viral (at Arg-667/Ser-668) serine-protease. Anand et al. site [2]. comprehensive review pathological consequences suggests phases infection [17].