ABCMdb

PMID: 9922378

Schultz BD, Singh AK, Devor DC, Bridges RJ
Pharmacology of CFTR chloride channel activity.
Physiol Rev. 1999 Jan;79(1 Suppl):S109-44., [PubMed]

Sentences

No. Mutations Sentence Comment

183 ABCC7 p.Arg347Asp Consistent kidney cells expressing wild-type or R347D CFTR. Login to comment 192 ABCC7 p.Arg347Asp Most importantly, DIDS is a known antagonist of purinergic receptors (53, 54, 56, 104, 105, had previously shown that the R347D mutation reduces the single-channel conductance, eliminates channel116, 249, 257, 366, 430, 443). Login to comment 242 ABCC7 p.Ser341Ala The likely site of action of DPC in this mutation of serine-341 to an alanine caused a fivefold increase in the KD at 0100 mV (wild type, 276 mM vs.tissue is the inhibition of cyclooxygenase, the enzyme responsible for prostaglandin synthesis. Login to comment 243 ABCC7 p.Ser341Ala Prostaglandins S341A, 1,251 mM). Login to comment 249 ABCC7 p.Ser341Ala ABCC7 p.Thr1142Phe ABCC7 p.Met1140Ile The interpretation of ar- residues immediately adjacent to S341, DPC bound with an affinity close to that of the wild-type channel (S341A-ylaminobenzoate inhibition of macroscopic Cl0 secretion is, at best, difficult because of their nonselectivity for Cl0 M1140I-T1142F). Login to comment 252 ABCC7 p.Thr1134Phe nine residue 1134 to a phenylalanine caused a threefold improvement in the affinity for DPC (T1134F, 74 mM). Login to comment 279 ABCC7 p.Gly551Asp In their studies, Xenopus oocytes The inhibition of PDE to elevate cAMP levels has been were injected with wild-type or mutant CFTR (e.g., the often intended reason for using alkylxanthines, espe- DF508, G551D) mRNA, and Cl0 current was measured in cially 3-isobutly-1-methyxanthine (IBMX; Fig. 3), in epithe- response to a stimulation cocktail including 10 mM for- lial transport studies. Login to comment 283 ABCC7 p.Gly551Asp pressing wild-type CFTR were nearly completely stimulated with 1 mM IBMX, but those expressing G551D orThe cAMP-mediated activation of Cl0 secretion has been recognized for more than 30 years (24, 154) and the DF508 CFTR required 5 mM IBMX to achieve complete stimulation. Login to comment 293 ABCC7 p.Gly480Cys There are, as a result of these drug development efforts, a number of isoform-specific PDEon to show that the missense mutation G480C associated with CFTR protein mislocalization was equally sensitive inhibitors that are in clinical use. Login to comment 313 ABCC7 p.Gly551Asp With the use of the halide-sensitive fluorophore SPQ assay, 4 mM IBMX ing cells, both an adenylyl cyclase agonist and milrinone were required to cause a response in vivo.was found to activate DF508 and G551D CFTR-mediated anion efflux. Login to comment 326 ABCC7 p.Gly551Asp ABCC7 p.Arg117His (0)-p-Bromotetramisole and IBMX also activated wild-type and the disease-are needed before one can conclude the stimulatory effects of milrinone are mediated by inhibition of class III causing mutant CFTR, R117H, G551D, and DF508 in cell-attached patches. Login to comment 367 ABCC7 p.Trp1282* In thisThese studies were subsequently repeated with similar results using NIH 3T3 cells expressing DF508 CFTR or nomenclature system, tyrosine phosphatases (PTP) are classified separately, whereas neither acid nor alkalinewild-type CFTR as well as with the human airway cell line IB3-1 derived from a DF508/W1282X CF patient (151). Login to comment 519 ABCC7 p.Gly551Asp It is tenuous to assess kinetic parameters for activa-have now reported that genistein potentiates the effect of maximally effective concentrations of IBMX (5 mM) and tion and inactivation processes involving enzymatically catalyzed reactions at room temperature if extrapolationsforskolin (10 mM) on G551D CFTR-expressing oocytes, whereas there is no effect on unstimulated or maximally to physiologically relevant conditions are intended. Login to comment 568 ABCC7 p.Gly551Asp Activation of the maxi K channel by dehydrosoyasaponin I was absolutely dependent on or G551D CFTR with NS004 in excised inside-out patches from mouse L cells recombinantly expressing CFTR (un-expression of the b-subunit (247), whereas activation by NS1619 was independent of b-subunit expression (107). Login to comment 579 ABCC7 p.Pro574His ABCC7 p.Arg560Thr A second possibility is that the phosporylation state of the channel obtainedsurements, that NS004 similarly activated an additional CFTR mutant, P574H, while failing to activate the CF- during activation by forskolin is distinct from that after activation of the channel by exogenous PKA/ATP in ancausing R560T or DI507 CFTR mutants (70). Login to comment 589 ABCC7 p.Gly551Asp We recently evaluated the effect of NS004 on both mined whether NS004 would stimulate transepithelial Cl0 secretion across monolayers of the colonic cell line T84.wild-type and G551D CFTR in the Xenopus oocyte expression system (327). Login to comment 595 ABCC7 p.Gly551Asp In contrast to this response, the benzimidazolone 1-ethyl-2-the results on DF508 CFTR (147), we found that after activation of G551D CFTR with a maximal concentration benzimidazolinone (1-EBIO; Fig. 3) stimulated a sustained charybdotoxin-sensitive Cl0 secretory response (93, 95).of forskolin (10 mM) plus IBMX (5 mM), the subsequent addition of NS004 (30 mM) induced an additional twofold Unfortunately, 1-EBIO has a low affinity for this effect P21-8/ 9j0e$$ja07 01-13-99 15:10:08 prsa APS-Phys Rev (EC50 Ç500 mM). Login to comment 621 ABCC7 p.Gly551Asp In contrast to these results, NS004 had no effect on in vivo nasal poten- attempted to identify drugs that are currently approved by the Food and Drug Administration for the treatmenttial difference measurements in the G551D mouse in the absence or presence of forskolin (Alton, personal commu- of other diseases that share structural similarity to the benzimidazolones. Login to comment 718 ABCC7 p.Gly551Asp Similarly, when added alone, NS004 tional mutations that are normally trafficked to the apical increased short-circuit current by only 0.4 mA/cm2 (n Å membrane in the intact epithelium (e.g., G551D). Login to comment 719 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp As out13) in DF508 expressing HBE, whereas in wild-type CFTR lined above, pharmacological agonists have been shown expressing HBE, NS004 increased short-circuit current by to activate the G551D mutant in Xenopus oocytes. Login to comment