Na + Cl -cotransport

In many epithelia Cl is transported transcellularly. Cl is taken up by secondary or tertiary active processes such as Na 2Cl K -cotransport, Na Cl -cotransport, HCOJ-Cl -exchange and other systems across one cell membrane and leaves the epithelial cell across the other membrane via Cl -channels. The driving force for Cl -exit is provided by the Cl -uptake mechanism. The Cl -activity, unlike that in excitable cells, is clearly above the Nernst potential [15,16], and the driving force for Cl -exit amounts to some 2(f-40mV. 

Sodium reabsorption continues in the distal convoluted tubule, which accounts for some 6 to 8% of the transport of sodium. The entry of Na+ across the apical cell membrane is mediated by Na+-Cl cotransport (Fig. 21.4). This protein is a distinct gene product that differs from the Na -K+-2C1 cotransporter in thick ascending limbs. 

Thiazide diuretics act in the distal convoluted tubule, where they block Na -Cl cotransport (Fig. 21.4). The Na" -Cl cotransport takes place on the luminal surface of distal convoluted tubules. Thus, to exert their diuretic action, the thiazides must reach the luminal fluid. Since the thiazide diuretics are largely bound to plasma proteins and therefore are not readily filtered across the glomeruli, access to the luminal fluid is accomplished by the proximal tubule organic acid secretory system. The drugs then travel along the nephron, presumably being concentrated as fluid is abstracted, until they reach their site of inhibitory action in the distal convoluted tubule. 

CI-/HC03- Anti porter CLIC Cl-channel Na+ Cl- Cotransporter 2... 

To date, coupling to Na+ and Cl- (with the exception of Na+/Cl cotransport) (Duffey et al., 1978 O Grady et al., 1987), seems to be confined to a restricted number of amino acids and amines. Of the 20 or so amino acids which are incorporated into proteins and transported by Na+ dependent routes, only glycine and glutamine uptake have been associated with a Cl- dependence (Vidaver, 1964a Weigensberg and Blostein, 1985 Mathew et al., 1993). 

Kunchaparty S, Palcso M, Berkman J et al (1999) Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman s syndrome. Am J Physiol 277 F643-F649... 

Normally, Na+ reabsorbed via the Na+/K+/2C1 transporter is transported back into the blood by a Na+/K+-ATPase exchange mechanism and by a Na+/Cl cotransporter, the excess Cl returning to the blood via passive diffusion. High intracellular K+ results in its back-diffusion across the luminal membrane, providing a positive potential (electrogenic) that drives reabsorption of both Ca2+ and Mg2+. 

ROC receiver-operating characteristic TSC thiazide sensitive Na" -Cl" cotransporter... 

Hydrochlorothiazide, indapamide, and metolazone (and many others) are organic acids that are both filtered and secreted and that inhibit the Na/Cl cotransporter on the luminal membrane of the distal convoluted tubule (DCT). 

Normally Na+ brought in by the Na/Cl cotransporter is exchanged for K+ via the pump on the basolateral membrane, K+ returning to the blood by back-diffusion. Cl ions return to the blood via diffusion through special channels. Ca2+ diffuses across the luminal membrane through channels regulated by PTH and is returned to the blood by a Ca/Na antiporter. 

Inhibition of the Na/Cl cotransporter increases the luminal concentrations of these ions. Hypokalemia and alkalosis occur consequent to the Na+ load downstream. Increased activity of the Ca/Na antiporter (regulated by PTH) leads to increased reabsorption of Ca2+ —> possible hypercalcemia. 

Na/Cl cotransporter in the limb of distal convoluted tubule. This action facilitates reabsorption of Ca2+, which is the basis for the use of thiazides in nephrolithiasis, and which can result in hypercalcemia. The increased load of Na+ in the collecting tubules leads to increased excretion of both K+ and H+, so hypokalemia and alkalosis may occur. 

The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. Initially, the drugs decrease extracellular volume by interacting with a thiazide-sensitive Na-Cl cotransporter in the kidney, leading to a fall... 

Fig. 2. Agents controlling the opening of Cl -channels. The structural formula, the name, the respeetive Cl -channel, and an appropriate reference are provided. (A) Note the similarity of GABA, taurine, and P-alanine. Note also that DPC and its analogues such as NPPB contain a -alanine backbone. (B) The structure of torasemide comes close to both DPC and furosemide or buraetanide. It blocks the Na ZCPK" -cotransporter with very high affinity and with lesser affinity also the TAL-Cl -channel. Note that IAA-94 is related to phenoxyaeetic acids (e.g., ethacrynic acid). Amidine is related to IAA-94 but it has a positive net charge. Amidine as well as IAA-94 block the ICOR channel at around lO mol/1 [63].

ATP-dependent ABC transporter family. However, it is atypical because it also contains a regulated chloride channel) In secretory epithelia of intestines, pancreas, lungs, sweat glands, and kidneys Cl enters epithelial cells through their basolateral surfaces using an Na+ + K+ + 2 Cl cotransporter and exits the cells through their apical surfaces using the CFTR channel. Absorptive epithelia also contain both the cotransporter and the CFTR channel, but Cl flows into the cells from the exterior surface, and the distribution of the cotransporter and CFTR between basolateral and apical surfaces is opposite to that in secretory cells.1... 

Valero MS, Garay RP, Gros P, Alda JO. 2006. Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and Na-K-Cl cotransporter NKCC1 isoform mediate the vasorelaxant action of genistein in isolated rat aorta. Eur J Pharmacol 544 126-131. 

Mayer SE, Sanders-Bush E. 5-Hydroxytryptamine type 2A and 2C receptors linked to Na+/K+/Cl cotransport. Mol Pharmacol 1994 45 991-996. 

O Grady, S.M., Palfrey, H.C., Field, M. (1987). Characteristics and functions of Na-K-Cl cotransport in epithelial tissues. Am. J. Physiol. 253, C177-C192. 

Inhibit the Na+/K+/Cr cotransport in ascending loop of Henle, resulting in retention of Na+, Cl" and water in the tubule. 

Mechanism of action The thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of Na+ by inhibition of a Na+/CI cotransporter on the luminal membrane (see Figure 23.2). They have a lesser effect in the proximal tubule. As a result, these drugs increase the concentration of Na+ and Cl- in the tubular fluid. The acid-base balance is not usually affected. [Note Because the site of action of the thiazide derivatives is on the luminal membrane, these drugs must be excreted into the tubular lumen to be effective. Therefore, with decreased renal function, thiazide diuretics lose efficacy.]... 

O Donnell ME, Duong V, Suvatne J, Foroutan S, Johnson DM (2005) Arginine vasopressin stimulation of cerebral microvascular endothelial cell Na-K-Cl cotransporter activity is VI receptor and [Ca] dependent. Am J Physiol Cell Physiol 289 C283-C292 Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 19 76-78... 

Figure I0.1 l). Potassium continues through the cell and leaves the basolateral membrane, possibly through a K-Cl cotransporter (2). The cotransport of Na, Cl, and K through the apical membrane is driven by an ATP-using pump in the basolateral membrane, namely Na,K-ATPase (3). The ions that are resorbed in the ascending limb of the loop of Henle are not followed by water, as this part of the renal tubule is not permeable to water however, these ions are in close proximity to the descending limb and thus enhance the passage of water out of the descending limb. Figure 10,13 also includes a K channel, which may be used in K resorption (4).

Oxalate is excreted primarily by the kidney. Oxalate is freely filtered at the glomerulus, where its concentration is normally 1 5 pM. One of the few physiologic functions of oxalate occurs in the proximal tubule where it plays a role in transcellular reabsorption of chloride (mainly present as sodium chloride). Cl entry across the apical membrane is mediated by Cl /oxalate exchange (oxalate is recycled from the tubular lumen to the cell by oxalate/ sulfate exchange, in parallel with Na /sulfate cotransport) [4]. Early studies of renal oxalate clearance using radio-labeled oxalate showed secretion in almost all subjects studied. More recent studies using direct measurement of serum and urine... 

An oral formula suitable for the correction of a variety of diarrheal fluid losses has been recommended by the World Health Organization (WHO). It consists of 90 mM Na, 20 mM K, 80 mM Cl, 30 mM HCO3, and 110 mM glucose. The glucose aids in intestinal absorption of sodium ions, because glucose transport is mediated by the Na-glucose cotransporter. Only low levels of sugar are used in oral replace-... 

Figure 18-5 Site 3 The Na transport systems responsible for the reabsorption of Na and Cl" in the water-impermeable distal convoluted tubule. Inhibitors of the luminal membrane-bound Na /CI cotransport system include the thiazide and thiazide-like diuretics.

The site of action of the thiazide and thiazide-like diuretics differs slightly from one species to another. In humans, however, it appears safe to conclude that all of these diuretics block the reabsorption of Na (and, thereby, the reabsorption of Cr) in the distal convoluted tubules by inhibiting the luminal membrane-bound Na /CI cotransport system (Fig. 18-5). Thus, all diuretics in this class arc responsible for the urinary loss of about 5 to 8% of the filtered load of Na. Although they differ in their potencies (i.c., the amount of drug needed to produce a given diuretic response), they are equally efficacious (i.c., they can all exert a similar maximal diuretic response).-"-As a result of their action at site 3, the thiazide and thia-zidc-like diuretics secondarily alter the renal excretion rate of important ions other than Na and Cl. Inhibition of Na ... 

The DAT, NET, and SERT are members of the family of Na+, Cl -dependent substrate-specific neuronal membrane transporters, which includes transporters for GABA, glycine, taurine, proline, betaine, and creatine (4-8). The putative structure of these transporters consists of 12 transmembrane domains with both the N- and C-terminal domains located within the cytoplasm. The mechanism of the transporter-mediated uptake of monoamines is believed to involve an electrogenic transport of monoamines by sequential binding and cotransport of Na+ and Cl-ions (4-8). 

Kinne, R Mount Desert Island Biological Salsbury Cove, ME Effects of cadmium and mercury on na-k-cl cotransporter in shark rectal gland. NIEHS... 

Cl cotransporter), (5) ion antiports (Na /H exchange), (6) facilitated diffusion (glucose via CLUT-1), (7) active transport (P-gp), (8) active antiport transport (Na /K ATPase), and (9) endocytosis (receptor as insulin or transferrin or adsorption mediated). Adapted from Huber etal. [47]. 

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