Mechanism of inactivation of sodium channels. (a) The hinged-lid mechanism. The intracellular loop connecting domains III and IV of the sodium channel is depicted as forming a hinged lid with the critical phenylalanine (F1489) within the IFM motif shown occluding the mouth of the pore during the inactivation process. The circles represent the transmembrane helices. (b) Three-dimensional structure of the central segment of the inactivation gate, as determined by multidimensional NMR. Side chains of the critical IFM motif residues (I1488, F1489 and M1490) are shown in yellow, and those of T1491, which is important for inactivation, and S1506, which is a protein-kinase-C-dependent phosphorylation site, are also indicated. Adapted from .