Regulatory interaction between CFTR and the SLC26 transporters.
Most epithelia that express CFTR secrete fluid rich in HCO3- and poor in Cl- that is generated by a CFTR-dependent Cl- absorption and HCO3- secretion process that when aberrant leads to human diseases such as cystic fibrosis and congenital chloride diarrhoea. Epithelial Cl- absorption and HCO3- secretion require expression of CFTR and other Cl- and HCO3- transporters in the luminal membrane of the secreting cells. Recent advances in understanding this critical epithelial function revealed that the luminal Cl- and HCO3- transporters are members of the SLC26 family. Characterization of several members of the family reveals that all characterized thus far are electrogenic with an isoform specific Cl-/HCO3- transport stoichiometry. In vivo these transporters exist in a transporting complex with CFTR. The SLC26 transporters and CFTR are recruited to the complex by binding to scaffolds containing PDZ domains. Upon stimulation and PKA-dependent phosphorylation of CFTR R domain, the R domain binds to the SLC26 transporter STAS domain. Interaction of the R and STAS domains results in a marked and mutual activation of CFTR and the SLC26 transporters. The significance of this mode of regulation to epithelial Cl- absorption and HCO3- secretion is obvious.
Shcheynikov
Nikolay
N
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA.
Ko
Shigeru B H
SB
Zeng
Weizhong
W
Choi
Joo Young
JY
Dorwart
Michael R
MR
Thomas
Philip J
PJ
Muallem
Shmuel
S
D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009865:Oocytes; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014981:Xenopus
D027321:Anion Transport Proteins; D001639:Bicarbonates; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator