Sodium channels in epithelia

Ion movements across epithelia can occur through the cells (transcellular route) or between the cells (extracellular route or shunt pathway). 

Epithelia like those of the small intestine, proximal renal tubule, and gall bladder are characterised by low or negligible transepithelial potential, low trans-epithelial resistance, and high hydraulic conductivity, and the shunt conductance is a large fraction of the total transepithelial conductance. These epithelia are able to transport large volumes of isotonic fluid. 

At the other extreme, some amphibian epithelia, such as frog abdominal skin and toad urinary bladder, behave as tight epithelia. These are characterised by a high transepithelial potential difference and resistance, and very low hydraulic conductivity, and the shunt conductance is only a small fraction of the total conductance. 

Between these two extreme types, there is an intermediate group of epithelia. 

The differences between the various types of epithelia do not seem to depend on the properties of the cell membranes themselves but rather on the variation in the properties of the tight junctions which join the epithelial cells together at their apical borders. When these tight junctions are not highly resistive, then the transepithelial potential is literally short-circuited through the tight junction. 

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It is important to realise that sodium channels in epithelia are different from those in excitable membranes. One clear piece of pharmacological evidence for this point of view is that epithelial sodium channels are relatively unaffected by TTX in high concentrations [147,148]. Furthermore, it is likely that there is more than one type of sodium channel in epithelia. For example, there are a number of pyrazine and pteridine compounds which block sodium transport by blocking sodium entry into the cells of the distal kidney tubule but do not block sodium entry into cells of the proximal tubules. 

MA Watsky, K Cooper, JL Rae. (1991). Sodium channels in ocular epithelia. Pfluegers Arch Eur J Physiol 419 454-459. 

Recently, Cl" channels have been discovered. These channels have no sequence relationship to the voltage-gated Na, and Ca channels. One such channel is involved in the disease, cystic fibrosis. In this disease, regulation of the channel is defective. The altered function of the channel in epithelia causes elevated levels of sodium and chloride ions in sweat and, through unknown processes, the accumulation of mucus in the respiratory tract and failure of exocrine secretion in glands, such as the pancreas. Blockage of airways leads to chronic lung infections that, with other effects of the Cl" transport deficiency, can be fatal. 

The wide distribution of sensitive tissues suggests that this type of channel is of considerable evolutionary antiquity as are the voltage-sensitive sodium channels of excitable membranes. Furthermore, throughout the remaining sections of this review, it will become clear that there are some, at least superficial, similarities between sodium channels in excitable membranes and those in epithelia. 

The affinity of the sodium channels in amphibian epithelia for amiloride and triamterene-like drugs is dependent on the ambient sodium concentration [l9l 192]. At 111 mM NaCl, the affinity is around 10 M" for amiloride and around 10 M for triamterene. 

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. 

Figure 14 Ion transport pathways responsible for water flux across intestinal epithelia. Sodium absorption in villus tip cells (left) stimulates water absorption, while chloride channel exit in crypt cells (right) stimulates water secretion.

From the point of view taken in this review, only those epithelia having sodium channels which can be blocked by defined chemical compounds, particularly the pyrazine carboxamides, will be discussed. 

As a general rule, channels blocked by the pyrazine compounds are found only in tight but not leaky epithelia. Thus pyrazine carboxamides block sodium entry into the cells of the kidney distal tubule [149], salivary duct [150], colon [ISl] and epididymis [152], but not into the cells of the small intestine of kidney proximal tubule. Sodium channels sensitive to pyrazine carboxamides are not confined either to epithelia or to mammalian cells. For example, sodium entry into the cells of frog skin epithelium [153], toad urinary bladder [154], chicken coprodeum, fish gills of some species [ISS], body wall of the leech [155] and crustacean gills [155] are also sensitive. In addition, there are reports that sodium entry sites in ova [3] and erythrocytes [156] are also susceptible to the effects of the pyrazine derivatives. 

The complexity of the changes of amiloride-binding site density, and hence presumably of sodium channels, which can take place in these epithelia are only just beginning to be understood. It is not surprising, therefore, that the ideal diuretic has not been found, for any perturbation at one part of the nephron is likely to affect the ambient sodium concentration at a distal part. The ensuing adaptive changes, plus the influence of hormones, are such as to produce complex patterns of excretion. 

The review of Dr A.W. Cuthbert discusses the properties of model membranes and epithelia, particulariy in relation to sodium channels and the transfer of ions across cell membranes. This exciting new field involving ionophores is being extensively studied by biological chemists at the present time. The second review by Dr G.J. Moody and Dr JD.R. Thomas describes some applications of ion-selective electrodes in medicine, an area in which membranes may lead to important advances. 

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