Platform R : Channel Regulation & Modulation

control ionic conditions in the cell and energise osmotic potentials, secondary transport schemes and ionotropic signalling. A surprising finding from the Naþ,Kþ-ATPase structure was the docking of two conserved tyrosine residues at the C-terminus of the alpha subunit into the transmembrane domain, hinting that this was a previously unidentified regulatory element. Several mutations causing human neurological syndromes have subsequently been mapped to the C-terminal structure element, also clearly indicating that conservation of the structure is important for pump function. Mutational analysis confirmed this and prompted our further analysis by electrophysiology and molecular dynamics simulations, which have shown a profound effect of the C-terminus on the electrogenic transport properties. We further propose that the C-terminal region forms a binding pocket that can be exploited for pharmacological intervention in cardiovascular and neurological disease.