Ion channels and lipid phosphatases adopt a transmembrane voltage sensor domain (VSD) that moves in response to physiological variations of the membrane potential to control their activities. However, the VSD movements and coupling to the channel or phosphatase activities may differ depending on various interactions between the VSD and its host molecules. BK-type voltage, Ca²(+) and Mg²(+) activated K(+) channels contain the VSD and a large cytosolic domain (CTD) that binds Ca²(+)and Mg²(+). VSD movements are coupled to BK channel opening with a unique allosteric mechanism and are modulated by Ca²(+) and Mg²(+) binding via the interactions among the channel pore, VSD and CTD. These properties are energetically advantageous for the pore to be controlled by multiple stimuli, revealing the adaptability of the VSD to its host molecules and showing the potential for intracellular signals to affect the VSD in order to modulate the function of its host molecules.