ABCMdb

PMID: 12802335

Reddy MM, Quinton PM
Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells.
Nature. 2003 Jun 12;423(6941):756-60., 2003-06-12 [PubMed]

Sentences

No. Mutations Sentence Comment

156 ABCC7 p.Arg117His In contrast, duct cells from heterozygous patients with R117H/DF508 mutant CFTR also lost most of the Cl2 conductance, yet retained significant HCO3 2 conductance. Login to comment 219 ABCC7 p.Arg117His CFTR-g Cl is decreased in R117H/DF508 ducts by ,85% and in DF508/DF508 ducts by ,100%. Login to comment 221 ABCC7 p.Arg117His Results are for n ¼ 10 ducts from eight normal subjects, n ¼ 9 ducts from two R117H/DF508 cystic fibrosis patients and n ¼ 8 ducts from three DF508/DF508 cystic fibrosis patients. Login to comment 223 ABCC7 p.Arg117His 0.01. b, Effect of R117H and DF508 CFTR mutations on glutamate/ATP-activated CFTR-g HCO3 . Login to comment 225 ABCC7 p.Arg117His The ducts from R117H/DF508 cystic fibrosis patients retained ,50% of CFTR-g HCO3 compared with normal controls. Login to comment 227 ABCC7 p.Arg117His Results are for n ¼ 10 ducts from eight normal subjects, n ¼ 9 ducts from two R117H/DF508 cystic fibrosis patients, and n ¼ 8 ducts from three homozygous DF508 cystic fibrosis subjects. Login to comment 247 ABCC7 p.Arg117His ABCC7 p.Arg117His In contrast, the R117H mutant CFTR, in which Arg 117 has been changed to His, is processed to the membrane and retains partial Cl2 conductance24,25 . Login to comment 249 ABCC7 p.Arg117His As shown in Fig. 4, DF508/DF508 ducts showed no detectable gCl response to glutamate, whereas the R117H/DF508 heterozygous ducts showed a significantly decreased (compared with the wild type), but clearly present, Cl2 conductance. Login to comment 250 ABCC7 p.Arg117His Equally compelling evidence is that only R117H/DF508 duct cells (but not DF508/ DF508 cystic fibrosis ducts) retained a significant CFTR-gHCO3 . Login to comment 251 ABCC7 p.Arg117His Thus, in the R117H/DF508 ducts we observed a decrease of nearly 85% in CFTR-gCl, whereas the same ducts retained about 50% of CFTR-gHCO3 (Fig. 4) compared with the wild type. Login to comment 252 ABCC7 p.Arg117His (Because the R117H mutation significantly decreases the gCl and open probability of the CFTR25 , the fact that at least 50% of normal gHCO3 seems to be present in the heterozygous ducts suggests that this mutation exhibits a gHCO3 that is equal to or even larger than normal. Login to comment 256 ABCC7 p.Arg117His The phenotypes of such mutations are broadly classified as 'mild`, in which patients fare better and retain pancreatic digestive function (for example R117H/DF508), and as 'severe`, in which patients fare worse and lack pancreatic function (for example DF508/DF508). Login to comment 258 ABCC7 p.Arg117His A role for CFTR in HCO3 2 transport is still not well defined27-29 , but the glutamate/ATP-activated CFTR-gHCO3 might reflect a crucial role in cystic fibrosis pathology and indicates a molecular basis for the observation that mild mutations such as R117H spare enough CFTR-gHCO3 to preserve pancreatic function in cystic fibrosis patients whereas severe mutations like DF508 do not, either because of poor conductance or poor expression in the plasma membrane23,24,26 (Fig. 4). Login to comment 259 ABCC7 p.Arg117His In heterologous systems, Cl2 /HCO3 2 exchange was reported to be dependent on the CFTR mutation, and R117H retained substantial ability to support the anion exchange func- tion29,30 . Login to comment