Cellular excitability is determined by the flow of different ions across the cell membrane, which is in turn controlled by the opening and closing of ion-permeable pores, the ion channels (Hille, 2001). For instance, in neurons, the opening of voltage-gated sodium channels allows the outward flow of intracellular sodium ions, so that the membrane potential is increased (depolarization) to fire the action potential, which encodes and delivers neuronal information. Upon membrane depolarization, voltage-gated potassium (Kv) channels are opened, so that the extracellular potassium ions flow into the cell to decrease the membrane potential and terminate one firing of the action potential (Sigworth, 1994). The two-pore potassium (K2P) channels, unlike Kv channels, are not activated by the membrane potential but by mechanical forces when the cell membrane is stretched (Honore, 2007). Such ‘leaky’ K2P channels control cell excitability by setting the resting potential in cells (Gonzalez et al., 2012). Therefore, understanding how K2P channels are opened or closed (gating) is critical.