CFTR-type channel

CFTR Cr channel multidrug transporter MDRl 3.A.2. H - or Na" -translocating F-type, V-type, A-type ATPase superfamily FqFi ATPase proton pump VqVj ATPase AqAi ATPase 3.A.3. P-type ATPase superfamily... 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

Mesoionic pyrimido[l,6- ]pyrimidine 94 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 9-Nitro-hexahydropyrimido[l,6- ]pyrimidines of type 222 have arthropodicidal activity <1997WO97/05145>. The zwitterionic pyrimido[l,6- ]pyrimidine-2-carboxylic acid 215 and related compounds are CFTR channel modulators with potential use to treat mucoviscidosis, asthma or diarrhea <2005W02005/039589>. 

CFTR potentiator (F508del-CFTR Ka= 0.11 pM, G551D-CFTR Ka= 1.2 pM) with 250-fold selectivity over the L-type voltage-dependent Ca2+ channel [52,53],... 

All ABC transporters have two nucleotide-binding domains (NBDs) and two transmembrane domains (Fig. 11-41). In some cases, all these domains are in a single long polypeptide other ABC transporters have two subunits, each contributing an NBD and a domain with six (or in some cases ten) transmembrane helices. Although many of the ABC transporters are in the plasma membrane, some types are also found in the endoplasmic reticulum and in the membranes of mitochondria and lysosomes. Most ABC transporters act as pumps, but at least some members of the superfamily act as ion channels that are opened and closed by ATP hydrolysis. The CFTR transporter (Box 11-3) is a Cl- channel operated by ATP hydrolysis. 

In non-CF HBE, forskolin stimulated a large, biphasic increase in Cl" secretion, whereas the response in AF508-HBE was monophasic and <5% of the wild-type response. The forskolin response in non-CF and AF508-HBE is blocked by CFTR inhibitors but not the Ca2+-activated Cl" channel blocker, DIDS, indicating that the response is due to CFTR activity in the apical membrane. Residual AF508-CFTR activity in the apical membrane of CF airway... 

Genotype a Channel density Channel gating Channel Wild-type CFTR Severity of conductance activity lung disease ... 

The primary function of the TMDs is to provide a pathway through which allocrites can cross the membrane. It is not difficult to imagine how such a pathway could readily be adopted for channel function (e.g., CFTR), but for receptor-type ABC proteins (such as SURl), the evolutionary step is less obvious. However, for all these functions, the TMDs appear to be the main determinants of specificity [3, 39, 40[. TMDs are much more variable in their amino acid sequences than the NBDs [15,41[. Hydropathy predictions, which have so far been borne out by later structural studies, imply multiple transmembrane a-helices, typically six per domain (see Section 1.2), but with many exceptions [3[. Eukaryotic ABC proteins in the C class (ABCC subdivision) frequently contain a whole extra TMD with five predicted transmembrane spans [7[. 

Interestingly, the voltage-gated CLC has classic channel characteristics, whereas CFTR has characteristics of an ion channel and a carrier. Apparently, in the case of CLC, the classical definition for channels and carriers is mixed, suggesting that the two types of ion transport mechanisms share common features. 

Colchicine has a narrow therapeutic index (i.e., the amount of drug that produces the desirable therapeutic effect is not much lower than the amount that produces an adverse effect). Its therapeutic effect depends on inhibiting tubulin synthesis in neutrophils, but it can also prevent tubulin synthesis (and, thus, cell division and other cellular processes) in other cells. Fortunately, neutrophils concentrate colchicine, so they are affected at lower intakes than other cell types. Neutrophils lack the transport protein P-glycoprotein, a member of the ABC cassette family (which includes the CFTR channel). In most other cell types, P-glycoprotein exports chemicals such as colchicine, thus preventing their accumulation. 

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