NaCl Cotransporter

Wilkinson DJ, Post MA, Venglarik C, Chang D, Dawson D (1993) Mercury blockade of thiazide-sensitive NaCl cotransport in flounder urinary bladder. Toxicol Appl Pharmacol 122 170-176... 

I have noted that NPPB is structurally related to loop diuretics of the furosemide (Fig. 2) type. These latter compounds bind to the Na 2CNK -cotransporter [16] and inhibit NaCl reabsorption in the TAL segment and NaCl secretion in epithelia such as the colonic crypt cell and rectal gland of Squalus acanthias [15]. We were able to show that only minor modification of the NPPB molecule on one side and of furosemide on the other led to compounds with altered selectivities [70,91-93]. One prototype of an intermediate blocker, i.e., a substance blocking both Na 2Cl K -cotransport and CP-channels, is torasemide (Fig. 2). Hence we have performed a systematic study in order to define the constraints defining the effectiveness of this class of substances [91]. 

Fig. 3. Cellular model for NaCl secretion ([16] e.g., in a colonic carcinoma cell). The symbols have the following meaning = (Na" + K )-ATPase (J = Na 2Cl K -cotransporter - = ion...

The NaCl transport system in the luminal membrane of the thick ascending limb is a Na+/K+/2CF cotransporter (Figure 15-4). This transporter is selectively blocked by diuretic agents known as "loop" diuretics (see below). Although the Na+/K+/2CF transporter is itself electrically neutral (two cations and two anions are cotransported), the action of the transporter contributes to excess K+ accumulation within the cell. This results in back diffusion of K+ into the tubular lumen and development of a lumen-positive electrical potential. This electrical potential provides the driving force for reabsorption of cations—including Mg2+ and Ca2+—via the paracellular pathway (between the cells). Thus, inhibition of salt transport in the thick ascending limb by loop diuretics causes an increase in urinary excretion of divalent cations in addition to NaCl. 

Only about 10% of the filtered NaCl is reabsorbed in the distal convoluted tubule. Like the thick ascending limb, this segment is relatively impermeable to water, and the NaCl reabsorption therefore further dilutes the tubular fluid. The mechanism of NaCl transport in the distal convoluted tubule is electrically neutral Na+ and O cotransport (Figure 15-5). This NaCl transporter is blocked by diuretics of the thiazide class. 

Cl dependence has been chiefly associated with amino acids which are not typical amino acids. These include taurine, -alanine, y-amino butyric acid (GABA), and betaine (Schon and Kelly, 1975 Kanner, 1978 Chesney, 1985 Turner, 1986 Kanner and Bendahan, 1990 Tiruppathi et al., 1992 Yamauchi et al., 1992). To a significant extent, some of these atypical amino acids (as well as glycine) are also neurotransmitters, although NaCl-coupled cotransport of these atypical amino acids also occurs outside the nervous system. The specificity for chloride is high. Of the anions tested (Cl-, Br-, I-, NO3, and glucuronate) as replacements, only sulphate has proved an effective substitute in a nominal way (25-50% of the activity in chloride see Turner, 1986). 

Except for meAIB no other truly specific substrate for an amino acid transport system has been defined. We deliberately chose not to discuss the properties of the putative different systems defined on the basis of selective inhibition. Instead the discussion has focussed on the nature of the ions coupled to amino acid uptake (e.g., Na+, NaCl, etc.), since it now appears from cloning data that the nature of the cotransported ions identifies different families of transporters (see below). 

Transport Cation-chloride cotransporter family Thiazide-sensitive NaCl Thiazide diuretics (inhibitors)... 

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