Lipid stress at play: mechanosensitivity of voltage-gated channels

Membrane stretch modulates the activity of voltage-gated channels (VGCs). These channels are nearly ubiquitous among eukaryotes and they are present, too, in prokaryotes, so the potential ramifications of VGC mechanosensitivity are diverse. In situ traumatic stretch can irreversibly alter VGC activity with lethal results but that is pathology. This chapter discusses the reversible responses of VGCs to stretch, with the general relation of stretch stimuli to other forms of lipid stress, and briefly, with some irreversible stretch effects (=stretch trauma). A working assumption throughout is that mechanosensitive (MS) VGC motions-that is, motions that respond reversibly to bilayer stretch-are susceptible to other forms of lipid stress, such as the stresses produced when amphiphilic molecules (anesthetics, lipids, alcohols, and lipophilic drugs) are inserted into the bilayer. Insofar as these molecules change the bilayer's lateral pressure profile, they can be termed bilayer mechanical reagents (BMRs). The chapter also discusses the MS VGC behavior against the backdrop of eukaryotic channels more widely accepted as "MS channels"--namely, the transient receptor potential (TRP)-based MS cation channels.