ENaC channels

Is this system relevant for hair cells It does not appear so. Indeed, there appear to be at least two broad classes of mechanoreceptors, one like those of C. elegans touch neurons that rely on DEG/ENaC channels, and another class that apparently relies on transient receptor potential (TRP) channels. As we will see later, circumstantial evidence suggests that hair cells use TRP channels. Other mechanoreceptors in vertebrates may be related to C. elegans touch cells. 

Fig. 1. Predicted membrane-spanning topology for mechanosensitive channels found in eukaryotes (TRPV, K2P, and DEG/ENaC channels) and bacteria (MscL and MscS). In addition to the transmembrane helices (represented as cylinders), other motifs present in these channels are designated as follows. The TRPV channels contain several cytoplasmic ankyrin domains (A) at the N terminus, and one pore-forming loop (P). K2P channels have two pore-forming loops and a self-interaction domain (SID) through which dimers are generated. DEG/ENaC sodium channels have a single pore-forming loop and three cysteine-rich domains (CRDs).

Goodman MB, et al. MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation. Nature 2002 415 1039-1042. 

I. Mano and M. Driscoll. 1999. DEG/ENaC channels A touchy superfamily that watches its ssXX Bioessays 21 568-578. (PubMed)... 

This autosomal dominant disorder is also characterized by a hypokalemic, hypomagnesemic metabohc alkalosis but, in contrast to Bartter s and Gitelraan s syndromes, there is hypertension and hyperreninism. The disease is due to activating mutations, which increase sodium transport through the ENaC channel with consequent enhanced kaliuresis (see Figure 45-8). 

The amiloride-sensitive Na+ channel (ENaC) is a cell membrane glycoprotein selective for sodium ions, which is composed of three subunits (a, (3 and y). Gating of sodium is inhibited by the diuretic amiloride. 

CFTR has a single-channel conductance of about 8 pS. It is present in the apical membranes of many epithelia. Its mutation leads to the potentially lethal disease cystic fibrosis. In addition to acting as a chloride channel, CFTR is also thought to regulate, e.g., the epithelial sodium channel ENaC, a molecularly unknown outwardly-rectifying chloride channel, and possibly also potassium channels and water channels. Some of these potential regulatory processes, however, are controversial. CFTR also acts as a receptor for bacteria. 

Hirschsprung s disease have ETB receptor mutations). The lack of ET-3/ETB receptor results in the absence of parasympathic ganglionic neurons in the myenteric plexus (Auerbach). Mice with an ET-3/ETB receptor disruption die within 2 weeks after birth. In transgenic mice, in which the expression of the ETB receptor is driven by the dopamine (3-hydroxylase promoter, normal myenteric plexus are present and no enteric disorder develops. These mice, however, show a salt-sensitive hypertension, which can be efficiently treated with amiloride, indicating that ETB receptors are involved in the regulation of natriuresis via the amilorid-sensitive sodium channel ENaC. 

ENaC mediates Na+ entry from the tubule lumen at the apical membrane and the Na+/K+ ATPase extrudes Na+ at the basolateral side. K+ channels are present on the basolateral and apical membrane. K+ channels at the apical membrane mediate K+ secretion into the tubular lumen. 

Several diseases involving dysregulation of MR function have been described although most of them are not causatively linked to the receptor itself. Pseudohypoaldosteronism for example is a syndrome of mineralocorticoid resistance characterized by urinary salt loss and dehydration. However, only very rarely mutations in the MR gene have been found in these patients so far. In most cases, this syndrome appears to be linked to defects in the subunits of the amiloride-sensitive sodium channel ENaC, a major target of mineralocorticoid action in the kidney. 

Disease-causing mutations are found in the cytoplasmic regulatory region of the (3 and y subunits of the epithelial sodium channel (ENaC) genes. In general, patients with Liddle s syndrome can be treated successfully with the ENaC inhibitor amiloride. 

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

Benos, D. J. and Stanton, B. A. (1999). Functional domains within the degenerin/ epithelial sodium channel (Deg/ENaC) superfamily of ion channels, J. Physiol., 520, 631-644. 

Staub, O., I. Gautschi, T. Ishikawa, K. Breitschopf, A. Ciechanover, L. Schild, and D. Rotin. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. Embo J. 16 6325-36.1997. 

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