H⁺ and Confined Water in Gating in Many Voltage Gated Potassium Channels: Ion /Water/Counterion/Protein Networks, and Added Protons to gate the Channel

The mechanism by which voltage gated ion channels open and close has been the subject of intensive investigation for decades. For a large class of potassium channels, and related sodium channels, the consensus has been that there is a large movement of positively charged segments of protein from voltage sensing domains that are mechanically connected to the gate through linker sections of the protein, opening and closing the gate. We have pointed out that this mechanism is based on evidence that has alternate interpretations, in which it is protons that move. It is known that water has properties in confined spaces, and at the surface of proteins, different from those in bulk water. In addition, there is the possibility of quantum properties that are associated with mobile protons, and with hydrogen bonds. In this review, we consider the evidence that indicates a central role for water, and the mobility of protons, as well as alternate ways to interpret the evidence for the standard model in which a segment of protein moves to accomplish gating. We discuss evidence that includes the importance of quantum effects and hydrogen bonding in confined spaces. K+ must be partially dehydrated in passing the gate, and the possible mechanism for doing so, involving counterions, and side chains, is considered; added protons could prevent this mechanism from operating, closing the channel. The implications of certain mutations have been unclear, and we offer consistent interpretations. There is evidence for proton transport in response to voltage change, including a similarity in sequence to the Hv1 channel; this appears conserved in a number of K+ channels. We also consider evidence for a switch in -OH side chain orientation in certain key serines and threonines.