Regulation of CFTR channel gating.

Findings outlined here support a complex model for the regulation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel gating that incorporates incremental protein kinase A (PKA) phosphorylation of CFTR at multiple sites which, in turn, differentially control the activity of CFTR's two nucleotide-binding domains (NBDs). The NBDs are functionally distinct: only one can respond to the non-hydrolyzable ATP analogue AMP-PNP, and then only after ATP has acted at the other. Moreover, the nature of the responses to AMP-PNP, and to the inorganic phosphate analogue orthovanadate, argues that ATP hydrolysis normally occurs at both NBDs, at one to initiate channel opening and at the other to initiate closing.