Correction of G551D-CFTR transport defect

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Correction of G551D-CFTR transport defect in epithelial

monolayers by genistein but not by CPX or MPB-07.

Zegarra-Moran O, Romio L, Folli C, Caci E, Becq F, Vierfond JM,

Mettey Y, Cabrini G, Fanen P, Galietta LJ.

This study compares the effect of three chemically unrelated

cystic fibrosis transmembrane conductance regulator (CFTR)

activators on epithelial cell monolayers expressing the

G551D-CFTR mutant.

We measured Cl(-) transport as the amplitude of short-circuit

current in response to the membrane permeable cAMP analogue

8-(4-chlorophenylthio)adenosine-3'-5'-cyclic monophosphate

(CPT-cAMP) alone or in combination with a CFTR opener. The

correction of G551D-CFTR defect was quantified by comparison

with maximal activity elicited in cells expressing wild type

CFTR. To this end we used Fisher rat thyroid (FRT) cells

transfected with wild type or G551D CFTR, and primary cultures

of human nasal epithelial cells.

In both types of epithelia, cAMP caused activation of Cl(-)

transport that was inhibited by glibenclamide and not by

4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid. After

normalising for CFTR expression, the response of FRT-G551D

epithelia was 1% that of wild type monolayers.

Addition of genistein (10-200 micro M), but not of

8-cyclopentyl-1,3-dipropylxanthine (CPX, 1-100 micro M) or of

the benzo[c]quinolizinium MPB-07 (10-200 micro M) to FRT-G551D

epithelia pre-treated with cAMP, stimulated a sustained current

that at maximal genistein concentration corresponded to 30% of

the response of wild type epithelia.

The genistein dose-response curve was bell-shaped due to

inhibitory activity at the highest concentrations. The

dose-dependence in G551D cells was shifted with respect to wild

type CFTR so that higher genistein concentrations were required

to observe activation and inhibition, respectively.

On human nasal epithelia the correction of G551D-CFTR defective

conductance obtained with genistein was 20% that of wild type.

The impressive effect of genistein suggests that it might

correct the Cl(-) transport defect on G551D patients.

British Journal of Pharmacology (Oct 4, 2002) 137(4), 504-512.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&

list_uids=12359632&dopt=Abstract

Becki

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