It is clear that no model that assumes an instantaneous reversal of the potential should fit the data. Instead, the model should carefully model the time dependence of the voltage generator. Here, we solve this issue by simply limiting the peak current to at least 1 ms after depolarization. One might also be able to force the model to predict the currents, and in such cases extra parameters are needed. This second model shifts the current peak to around 1 ms after depolarization, appropriately fitting the data. Ultimately, better time resolution of the voltage is needed to fully resolve this issue. Assuming a reverse or inward ����tail���� current proportional to the number of open channels during hyperpolarization is enough to predict tail currents that are in full agreement with experimental measurements. We note that Hodgkin and Huxley model suggested that tail currents were the result of channels that remained open at the end of the first pulse, tail currents are mostly due to channels that were first inactivated and reopened in their way to the closed state, as first suggested by Demo and Yellen. A striking prediction of the model is that if we assume that the scaling of the parameters described in Fig. 2C are OSI-774 EGFR/HER2 inhibitor appropriate for any voltage, then ramping the membrane potential at a rate slower than k1 leads to insignificant ionic currents. The reason for this is that, for Vm.250 mV, the N-terminal peptide will block the ion channel before reaching the fully depolarized state. Hence, ionic currents are predicted to strike only if the reversal of the membrane potential is faster than the blocking rate. Interestingly, this phenomenon was apparently last quantitatively described by Hodgkin and Huxley. A unique feature of our model is that we show that each of the six states is consistent with the structural constraints of the Shaker channel. In fact, the states correspond to the classical open, closed and blocked state, where each of these states can be in either a polarized or hyperpolarized substate. Collectively, this study provides insights pertinent to a new level of understanding of the kinetic coupling of ionic currents. In agreement with experiments, we find a late stage voltage-independent rate of channel closing, whose limiting step during hyperpolarization, the transition between HBRHO where k21,,kon; the Kinase Inhibitor Library in vivo molecular mechanism of the slow inward tail current; without any sophisticated modeling technique, ionic currents have probed the validity of the model of the ����down���� state that rotates the S1 TM domain, see Caterall��s and Jan��s models ; finally, the role of the S1-T1 linker as a key regulator of Kv-like channels is further supported by its conservation across distant species, as well as the recently reported extended state of this domain.