THE SUBSTITUTED BENZIMIDAZOLONE NS004 IS AN OPENER OF THE CYSTIC-FIBROSIS CHLORIDE CHANNEL

Cystic fibrosis is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs. Ep ithelial cells of cystic fibrosis patients have a decreased capacity t o secrete chloride in response to cAMP-mobilizing agents because of th e mutation of a single gene. The gene product, the cystic fibrosis tra nsmembrane conductance regulator or CFTR, is a chloride channel. The m ost frequent mutation is a deletion of phenylalanine in position 508 ( DELTAF08-CFTR) that reduces both the expression of the CFTR protein at the cell surface, and the activity of the Cl- channel. This work pres ents the properties of NS004, a substituted benzimidazolone, which is the first activator of normal and mutant CFTR-associated chloride chan nels to be described. NS004 activated CFTR and DELTAF508-CFTR Cl- chan nels expressed in Xenopus oocytes, and increased I-125 efflux (via the Cl- channel) from Vero cells expressing CFTR and DELTAF508-CFTR. Appl ication of NS004 to the external side of outside-out patches excised f rom these CFTR- and DELTAF508-CFTR-expressing cells induced a marked a nd reversible increase in channel activity.