Abstract
Aberrant HCO3− transport is a hallmark of cystic fibrosis (CF) and is associated with aberrant Cl−-dependent HCO3− transport by the cystic fibrosis transmembrane conductance regulator (CFTR). In a previous work, we showed that the bulk of CFTR activated Cl−-dependent HCO3− transport occurs as a coupled Cl−/HCO3− exchange and identitied the members of SLC26 anion exchangers as proteins activated by CFTR(EMBO J 2002, 21:5662). In the present study when co-expressed in HEK293 cells, we found that the first and the second half of the CFTR with Regulatory(R) domain [TM1+NBD1+R, R+TM2+NBD2] activated Down-regulated in adenoma (DRA; SLC26A3) anion exchanger, a gene responsible for a congenital chloride diarrhea. In contrast, DRA activated CFTR whole cell chloride current by ~3 fold although the amount of the expressed CFTR in the plasma membrane remained unchanged. DRA increased CFTR Po (open probability) and NPo by ~2.5 fold and 5 fold, respectively. In addition, a novel SLC26 transporter domain, DRA STAS domain interacts with CFTR and markedly increased the Po and NPo of CFTR by ~3 fold and 7 fold, respectively. Significantly, disease-associated mutant DRA I668ins and its STAS domain (DRA STAS I668ins) inhibited the CFTR chloride current. Taken together, these findings provide a molecular mechanism for CFTR-dependent HCO3− transport. Mutual regulatory interactions of CFTR and the member of SLC26 transporter may explain the aberrant HCO3− transport observed in CF. [Jpn J Physiol 54 Suppl:S88 (2004)]
