Voltage-Sensing Domain of Voltage-Gated Proton Channel Hv1 Shares Mechanism of Block with Pore Domains

Liang Hong, Medha M. Pathak, Iris H. Kim, Dennis Ta, Francesco Tombola
2013 Neuron  
Voltage-gated sodium, potassium, and calcium channels are made of a pore domain (PD) controlled by four voltage-sensing domains (VSDs). The PD contains the ion permeation pathway and the activation gate located on the intracellular side of the membrane. A large number of small molecules are known to inhibit the PD by acting as open channel blockers. The voltage-gated proton channel Hv1 is made of two VSDs and lacks the PD. The location of the activation gate in the VSD is unknown and open
more » ... l blockers for VSDs have not yet been identified. Here, we describe a class of small molecules which act as open channel blockers on the Hv1 VSD and find that a highly conserved phenylalanine in the charge transfer center of the VSD plays a key role in blocker binding. We then use one of the blockers to show that Hv1 contains two intracellular and allosterically coupled gates.
doi:10.1016/j.neuron.2012.11.013 pmid:23352164 pmcid:PMC3559007 fatcat:22hpnrwhj5edhdpxuggvexogra