Gating Dynamics, Regulation and Pharmacology of the CFTR Anion Channel

Abstract

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) belongs into the C subfamily of ABC proteins, but its transmembrane domains (TMDs) form an anion selective channel pore which is under the control of its three cytosolic domains. Phosphorylation by protein kinase A (PKA) of multiple serines in the unique regulatory (R) domain is a prerequisite for channel activity, and gating of phosphorylated channels is driven by ATP binding and hydrolysis at the two cytosolic nucleotide binding domains (NBDs). Anion transport through CFTR is indispensable for the salt-water balance of epithelia lining the lung, gut, pancreatic duct, and sweat duct, and mutations that impair CFTR surface expression, gating, or anion permeation through the open pore cause cystic fibrosis (CF). In the past decade small molecule potentiator drugs, that enhance the open probability of mutant CFTR channels, have found their way to the clinics, and high-resolution structures of the CFTR protein in various conformations, obtained by electron-cryomicroscopy, have shed unprecedented light on CFTR molecular mechanisms. This talk will focus on recent advances in our understanding of three aspects of CFTR function: the dynamics of the pore opening transition in phosphorylated ATP-bound channels, the kinetic mechanism of the potentiator drug Vx-770 (ivacaftor), and the molecular mechanism of physiological gating regulation through interaction of CFTR with the catalytic subunit of PKA.