Epithelial sodium channel

The epithelial sodium channel (short: ENaC, also: sodium channel non-neuronal 1 (SCNN1) or amiloride sensitive sodium channel (ASSC)) is a membrane-bound ion-channel that is permeable for Li+-ions, protons and especially Na+-ions. It is a constitutively active ion-channel. It is arguably the most selective ion channel.

The apical membrane of many tight epithelia contains sodium channels that are primarily characterised by their high affinity to the diuretic blocker amiloride. These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis. In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception.

Location and function
ENaC is located in the apical membrane of polarized epithelial cells particularly in the kidney (primarily in the collecting tubules), the lung and the colon. It is involved in the transepithelial Na+-ion transport, which it accomplishes together with the Na+/K+-ATPase.

It plays a major role in the Na+- and K+-ion homeostasis of blood, epithelia and extraepithelial fluids by resorption of Na+-ions. The activity of ENaC in colon and kidney is modulated by the mineralcorticoid aldosterone. It can be blocked by either triamterene or amiloride, which are used medically to serve as diuretics. In the kidney it is inhibited by atrial natriuretic peptide, causing natriuresis and diuresis.

ENaC can furthermore be found in taste receptor cells, where it plays an important role in salt taste perception. In rodents virtually the entire salt taste is mediated by ENaC, whereas it seems to play a less significant role in humans: about 20 percent can be accredited to the epithelial sodium channel.

It has been suggested that it may be a ligand-gated ion channel.

Structure


ENaC consists of three different subunits: α, β, γ. The stoichiometry of these subunits is still to be verified, but ENaC is very likely to be a heterotrimeric protein like the recently analyzed acid-sensing ion channel 1 (ASIC1), which belongs to the same family. Each of the subunits consists of two transmembrane helices and an extracellular loop. The amino- and carboxy-termini of all polypeptides are located in the cytosol.

Structurally, the proteins that belong to this family consist of about 510 to 920 amino acid residues. They are made of an intracellular N-terminus region followed by a transmembrane domain, a large extracellular loop, a second transmembrane segment and a C-terminal intracellular tail.

δ-subunit
In addition there is a fourth, so-called δ-subunit, that shares considerable sequence similarity with the α-subunit and can form a functional ion-channel together with the β- and γ-subunits. Such δ, β, γ-ENaC appears in pancreas, testes and ovaries. Their function is yet unknown.

Families
Members of the epithelial Na+ channel (ENaC) family fall into four subfamilies, termed alpha, beta, gamma and delta. The proteins exhibit the same apparent topology, each with two transmembrane (TM) spanning segments, separated by a large extracellular loop. In most ENaC proteins studied to date, the extracellular domains are highly conserved and contain numerous cysteine residues, with flanking C-terminal amphipathic TM regions, postulated to contribute to the formation of the hydrophilic pores of the oligomeric channel protein complexes. It is thought that the well-conserved extracellular domains serve as receptors to control the activities of the channels.

Vertebrate ENaC proteins are similar to degenerins of Caenorhabditis elegans : deg-1, del-1, mec-4, mec-10 and unc-8. These proteins can be mutated to cause neuronal degradation, and are also thought to form sodium channels.

Genes
The exon–intron architecture of the three genes encoding the three subunits of ENaC have remained highly conserved despite the divergence of their sequences.
 * SCNN1A, SCNN1B, SCNN1G, SCNN1D

There are four related amiloride sensitive sodium channels:
 * ACCN1, ACCN2, ACCN3, ACCN4

Clinical significance
ENaC interaction with CFTR is arguably of the most important pathophysiological relevance in cystic fibrosis. CFTR is a membrane bound protein responsible for Chloride transport and defects in this protein cause cystic fibrosis.

In a (normal) sweat gland, CFTR has an stimulatory effect on ENaC. In cystic fibrosis, the CFTR channel does not work, so ENaC is also inhibited. Hence, there's less Na+ reuptake and the sweat of the patient can physically be tasted to be salty. This was a common technique to help diagnose the disease prior to modern methods.

In the (normal) airway, CFTR has an inhibitory effect on ENaC (this is their typical interaction). Normally, chloride is secreted into the airway mucous and sodium is absorbed. In cystic fibrosis, chloride is not secreted and since ENaC is not inhibited, Na+ absorption markedly increases. Lower salt in the mucous results in very thick and viscous mucous, containing far less water than normal (water follows ion movement via osmosis). This thick mucous blocks oxygen exchange and causes difficulty breathing, and leaves the lungs unable to flush the mucous (and trapped bacteria) out of the lungs leading to increased respiratory tract diseases.

Units β and γ are associated with Liddle's syndrome.

Amiloride and triamterene are potassium-sparing diuretics which act as epithelial sodium channel blockers.