Epithelia, sodium channels

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. 

Figure 1.15. Density of sodium channels in frog skin epithelium versus the level of sodium transport which can be maintained by the tissue. Sodium channel density was determined by measuring / Clamiloride binding. Sodium transport was measured as the damping current required to maintain the transepithelial potential at zero, with a low sodium solution fl.l mMj bathing the mucosal surface. The six epitheHa represented by the extreme right-hand point had been deprived of sodium for 1 week. The values for 11 untreated skins and for 4 sham-treated skins are shown at the right. Mean values and standard errors are illustrated. Redrawn from Cuthbert and Shum //97/...

The olfactory epithelium is composed of basal, neuronal (olfactory), and susten-tacular (support) cells (Figure 27.3). The portion of each olfactory cell that responds to the olfactory chemical stimuli is the cilia. The odorant substance first diffuses into the mucus that covers the cilia and then binds to specific receptor proteins in the membrane of each cilium. Next, receptor activation by the odorant activates a multiple molecules of the G-protein complex in the olfactory epithelial cell. This, in turn, activates adenylyl cyclase inside the olfactory cell membrane, which, in turn, causes formation of a greater multitude of cAMP molecules. Finally, the cAMP molecules trigger the opening of yet an even greater multitude of sodium ion channels. This amplification mechanism accounts for the exquisite sensitivity of the olfactory neurons to extremely small amounts of odorant. The olfactory epithelium is an important target of certain inhaled toxicants. Certain metals, solvents, proteins, and viruses are transported to the brain via transport from the olfactory epithelium to the olfactory tract and exert neurotoxicity. 

Fig. I. The olfactory epithelium. A. Schematic illustration of the olfactory epithelium showing the major cell types. Inset shows the location of putative 7TM odorant receptors on cilia of ORNs. B. Hypothesized olfactory receptor-transduction mechanisms. Current evidence suggests that odor molecules bind to specific 7 transmembrane receptor (7TMr) proteins located in the cilia of ORNs. These 7 TMrs are thought to be coupled to G-proteins that activate either adenyl cyclase (AC) to generate cyclic AMP (cAMP) or phospholipase C (PLC) to generate phosphatidyl inositol (IP3). These second messengers open channels that admit calcium ( Ca ) or sodium (Na ) into the cilium. These ions lead to membrane depolarization and may modulate intracellular free Ca levels, both of which lead to the generation of action potentials that are conducted along ORN axons to the olfactory bulb.

For example, when tissues were deprived of sodium for several days the site density increased 3-fold from around 250//im, but more importantly there was a proportional increase in the level of transport which was maintained by the epithelium [197] (Figure 1.15). This effect seems an important homeostatic device possessed by the cell to deal with exposures to divergent sodium concentrations. Furthermore, the result indicates that the entry step, rather than the exit step from the epithelium which requires sodium pumping, is the rate determinant of the level of transport. The time course of the effect of sodium deprivation may mean that it is dependent on the de novo synthesis of new membrane permeases. However, increasing the membrane potential across the mucosal face of the cells causes an immediate appearance of new channels, while reducing the potential does the converse [198], indicating that there are binding sites (and... 

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