CFTR C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
CFTR, a 12TM, ABC transporter-type protein, is a cAMP-regulated epithelial cell membrane Cl- channel involved in normal fluid transport across various epithelia. Of the 1700 mutations identified in CFTR, the most common is the deletion mutant ΔF508 (a class 2 mutation) which results in impaired trafficking of CFTR and reduces its incorporation into the plasma membrane causing cystic fibrosis (reviewed in [3]). Channels carrying the ΔF508 mutation that do traffic to the plasma membrane demonstrate gating defects. Thus, pharmacological restoration of the function of the ΔF508 mutant would require a compound that embodies 'corrector' (i.e. facilitates folding and trafficking to the cell surface) and 'potentiator' (i.e. promotes opening of channels at the cell surface) activities [3]. In addition to acting as an anion channel per se, CFTR may act as a regulator of several other conductances including inhibition of the epithelial Na channel (ENaC), calcium activated chloride channels (CaCC) and volume regulated anion channel (VRAC), activation of the outwardly rectifying chloride channel (ORCC), and enhancement of the sulphonylurea sensitivity of the renal outer medullary potassium channel (ROMK2), (reviewed in [7]). CFTR also regulates TRPV4, which provides the Ca2+ signal for regulatory volume decrease in airway epithelia [2]. The activities of CFTR and the chloride-bicarbonate exchangers SLC26A3 (DRA) and SLC26A6 (PAT1) are mutually enhanced by a physical association between the regulatory (R) domain of CFTR and the STAS domain of the SCL26 transporters, an effect facilitated by PKA-mediated phosphorylation of the R domain of CFTR [5].
Channels and Subunits
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CFTR
C
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How to cite this family page
Database page citation:
CFTR. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=129.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.
In addition to the agents listed in the table, the novel small molecule, ataluren, induces translational read through of nonsense mutations in CFTR (reviewed in [10]). Corrector compounds that aid the folding of DF508CFTR to increase the amount of protein expressed and potentially delivered to the cell surface include VX-532 (which is also a potentiator), VRT-325, KM11060, Corr-3a and Corr-4a see [12] for details and structures of Corr-3a and Corr-4a). Inhibition of CFTR by intracellular application of the peptide GaTx1, from Leiurus quinquestriatus herbareus venom, occurs preferentially for the closed state of the channel [4]. CFTR contains two cytoplasmic nucleotide binding domains (NBDs) that bind ATP. A single open-closing cycle is hypothesised to involve, in sequence: binding of ATP at the N-terminal NBD1, ATP binding to the C-terminal NBD2 leading to the formation of an intramolecular NBD1-NBD2 dimer associated with the open state, and subsequent ATP hydrolysis at NBD2 facilitating dissociation of the dimer and channel closing, and the initiation of a new gating cycle [1,6]. Phosphorylation by PKA at sites within a cytoplasmic regulatory (R) domain facilitates the interaction of the two NBD domains. PKC (and PKGII within intestinal epithelial cells via guanylinstimulated cyclic GMP formation) positively regulate CFTR activity.