Chapter 27 - Why are So Many Ion Channels Mechanosensitive?

Abstract

Reports of stretch-sensitive channels started appearing in the mid-1980s. Briefly, the unidentified mechanosensitive (MS) channels were seen as representatives of a new subclass of channels. There were speculations that “mechano-gating motifs” would soon be discovered. Gradually, however, it emerged that channels showing no mechanosensitivity are the outliers and it became clear that gating energy is supplied by bilayer deformations. Over the last decade, what has been particularly helpful in clarifying the role of bilayer mechanics in the mechanosensitive responses of diverse eukaryotic channels have been converging advances on three fronts: (1) high resolution structure/function data for voltage-gated channels (VGCs); (2) the demonstration that VGCs are inherently mechanosensitive; and (3) experimental and computational data showing how mechanosensitivity emerges from the energetics at the interface of dynamically structured bilayers and dynamically structured proteins. An ongoing task is to establish if and where the reversible mechanosensitive responses of ion channels are physiologically relevant; do they, for instance, contribute to cardiac mechano-electric feedback? Also enormously important, in my view, is to learn what the irreversible MS behaviors of channel reveal about the pathological membrane phenomena associated with trauma, ischemia, inflammation and, in fact, any condition where channel-bearing membranes undergo irreversible structural changes. One likely payoff: “smarter” drugs designed to target not simply channel-X, but channel-X in bilayer-structure-Y – say, leaky sodium channel in nodes of Ranvier where lipid packing has become disorderly and where leaflet asymmetry has been compromised by traumatic brain injury.