Oral Presentation 2014 International Biophysics Congress

Kir channel regulation: A changing perspective on gating (#128)

Jacqueline Gulbis 1 2 , Oliver B. Clarke 1 2 , Alessandro T. Caputo 1 2 , Adam P. Hill 3 , Jamie I. Vandenberg 3 , David M. Miller 1 2 , Brian J. Smith 1 2
  1. Walter + Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  3. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

Abnormally functioning ion channels are implicated in a host of conditions that upset neurological, cardiac, endocrine and other functions. These almost invariably arise as a consequence of defects in the specific mechanisms that switch ion currents on and off. Considerable international effort has gone into identifying these “gating” mechanisms and ascertaining how gating is triggered and regulated.
A fundamental difference between K+ and other cations is the propensity of K+ to shed its hydration shell and interact directly with the pore. The ion selectivity filter, a linear series of K+ coordination sites extending through the outer leaflet of the bilayer, is a distinctive signature of K+ channels. It is also one of two regions of the ion conduction pathway implicated in permeation gating - the other being a constriction close to the intracellular face of the channel. While research into selectivity filter gating has primarily focused on C-type inactivation, our data suggest that it is not limited to this.
Based on a study of inward rectifier K+ (Kir) channels, we consider structural evidence for interdependent processes of activation and allosteric switching. By using only one type of K+ channel, structural differences can be directly attributed to changes in functional status. This is important for pinpointing regions of the protein that alternate between discrete conformations and revealing changes in different regions of the protein that are correlated. The comparison suggests activation gating is triggered by conformational changes in the cytosolic assembly and argues that activation and inactivation at the selectivity filter occur independently of other changes in the permeation pathway.