“…The measured observation is that the voltage sensor required stronger repolarization to return to its resting position and to close the pore gate than was required to activate it ( Figure 3A). Similar hysteresis behavior has been reported in a broad collection of channels including sodium channels of the squid giant axon and NaChBac (Bezanilla et al, 1982;Kuzmenkin et al, 2004), calcium channels (Brum and Rios, 1987;Brum et al, 1988;Shirokov et al, 1992), potassium channels, such as KcSA (Tilegenova et al, 2017), Shaker (Haddad and Blunck, 2011;Lacroix et al, 2011;Labro et al, 2012;Priest et al, 2013), Kv1.2 (Labro et al, 2012), Kv3.1 (Labro et al, 2015), Kv7.2/7.3 (Corbin-Leftwich et al, 2016), Kv11.1 (hERG) (Piper et al, 2003;Tan et al, 2012;Hull et al, 2014;Goodchild et al, 2015;Thouta et al, 2017;Shi et al, 2019), Kv12.1 (Dierich et al, 2018), and HCN channels (Elinder et al, 2006;Bruening-Wright and Larsson, 2007). In HCN channels, the term mode-shift has been used to describe the hysteresis in the voltage-dependence of activation and deactivation in response to prolonged depolarization (Elinder et al, 2006), and the terms hysteresis and mode-shift are often used to describe the separation between the voltagedependence of Kv channel activation and deactivation.…”