The molecular mechanisms involved in slow C-type inactivation are not clear yet but may involve structural rearrangements in the outer pore domain paralleled by impaired K+ coordination in the selectivity filter. The mechanism of KCNQ1 inactivation and its modulation by external K+ are dissimilar to the mechanism described for C- type inactivation in Shaker-like K+ channels. Further, inactivation of wild-type (WT) KCNQ1 channels becomes evident only in the characteristic hooked tail currents which reflect recovery from inactivation. We use a combination of functional-structural analysis combined with mathematical and 3D-structural modeling to gain insights into the structural rearrangements during KCNQ1-inactivation. We show that the Kv7.1 a-subunits act in a concerted way to initiate KCNQ1-inactivation.