H and Confined Water in Gating in Many Voltage-Gated Potassium Channels: Ion/Water/Counterion/Protein Networks and Protons Added 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 the gating current preceding the main ionic current 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, thus opening and closing the gate. We have pointed out that this mechanism is based on evidence that has alternate interpretations in which protons move. Very little literature considers the role of water and protons in gating, although water must be present, and there is evidence that protons can move in related channels. 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 the hydrogen bonds that must be present in the pore; these are likely to be of major importance in gating. 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 of the standard model in which a segment of protein moves. We discuss evidence that includes the importance of quantum effects and hydrogen bonding in confined spaces. K must be partially dehydrated as it passes the gate, and a possible mechanism for this is considered; added protons could prevent this mechanism from operating, thus closing the channel. The implications of certain mutations have been unclear, and we offer consistent interpretations for some that are of particular interest. Evidence for proton transport in response to voltage change includes a similarity in sequence to the H1 channel; this appears to be 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.