Cotransport

FIGURE 10.16 The H+,lO-ATPase of gastric mucosal cells mediates proton transport into the stomach. Potassimn ions are recycled by means of an associated K /Cl cotransport system. The action of these two pnmps results in net transport of and Cl into the stomach. 

Sodium-dependent glucose cotransporters (SGLT) are located on small-intestine and kidney brush-border membranes. SGLT1, SGLT2, and SGLT3 are... 

SGLT2 is a low-affinity, high capacity sodium-glucose cotransporter located in the early proximal convoluted tubule SI segment. SGLT2 comprises 13... 

The thiazide sensitive NaCI cotransporter (NCC) is the major pathway of NaCI entry in the distal convoluted tubule. Like NKCC2, NCC contains 12 putative transmembrane domains and long intracellular amino-and carboxy-tails. NCC and NKCC as well as the KC1 cotransporter KCC are members of the same gene family and have considerable homology. 

The bumetanide-sensitive Na+, K+, 2CF cotransporter (NKCC) mediates the electroneutral uptake of chloride across epithelial cell membranes and is found in both absorptive and secretory epithelia (airways, salivary gland). NKCC exists in two isoforms, the secretory isoform NKCC1, and the absorptive isoform NKCC. 

NKCC is a heavily glycosylated protein with 12 putative membrane-spanning regions. Thirty percent of the sodium that is filtered by renal glomeruli is reabsorbed by Na-K-2C1 cotransport in the ascending limb of Henle in the nephron. Na-K-2C1 cotransport is a target of all loop diuretics. 

Tyrosine hydroxylase 1 Thiazide diuretics, a group of drugs with moderate diuretic activity, includes hydrochlorothiazide, chlorthalidone, and xipamide. They decrease active reabsorption of sodium and accompanying chloride by binding to the chloride site of the electroneutral Na+/CF cotransport system in the distal convoluted tubule and inhibiting its action. 

Baringhaus KH, Matter H, Stengelin S and Kramer W. Substrate specificity of the ileal and the hepatic Na /bile acid cotransporters of the rabbit. II. A reliable... 

D QSAR pharmacophore model for the ileal Na /bile acid cotransporter. J Lipid Res 1999 40 2158-68. 

The free fatty acid uptake by tissues is related directly to the plasma free fatty acid concentration, which in turn is determined by the rate of lipolysis in adipose tissue. After dissociation of the fatty acid-albumin complex at the plasma membrane, fatty acids bind to a membrane tty acid transport protein that acts as a transmembrane cotransporter with Na. On entering the cytosol, free fatty acids are bound by intracellular fatty acid-binding proteins. The role of these proteins in intracellular transport is thought to be similar to that of serum albumin in extracellular transport of long-chain fatty acids. 

Transport systems can be described in a functional sense according to the number of molecules moved and the direction of movement (Figure 41-10) or according to whether movement is toward or away from equilibrium. A uniport system moves one type of molecule bidirectionally. In cotransport systems, the transfer of one solute depends upon the stoichiometric simultaneous or sequential transfer of another solute. A symport moves these solutes in the same direction. Examples are the proton-sugar transporter in bacteria and the Na+ -sugar transporters (for glucose and certain other sugars) and Na -amino acid transporters in mammalian cells. Antiport systems move two molecules in opposite directions (eg, Na in and Ca out). 

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. 

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].

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...

Sodium/glucose cotransporter (rabbit intestinal brush borders)1641 Stearylcoenzyme A desaturase (rat liver microsomal)[651 Subtilopeptidase amylosacchariticus[661 Succinate dehydrogenase (mitochondrial)1671... 

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