Membrane potential as master regulator of cellular mechano-transduction

Abstract

Membrane potential is a property of all living cells1. However, its physiological role in nonexcitable cells is poorly understood. Resting membrane potential is typically considered fixed for a given cell type and under tight homeostatic control2, akin to body temperature in mammals. Contrary to this widely accepted paradigm, we found that membrane potential is a dynamic property that directly reflects tissue density and mechanical forces acting on the cell. Serving as a quasi-instantaneous, global readout of density and mechanical pressure, membrane potential is integrated with signal transduction networks by affecting the conformation and clustering of proteins in the membrane3,4, as well as the transmembrane flux of key signaling ions5,6. Indeed, we show that important mechano-sensing pathways, YAP, Jnk and p387–121314, are directly controlled by membrane potential. We further show that mechano-transduction via membrane potential plays a critical role in the homeostasis of epithelial tissues, setting tissue density by controlling proliferation and cell extrusion of cells. Moreover, a wave of depolarization triggered by mechanical stretch enhances the speed of wound healing. Mechano-transduction via membrane potential likely constitutes an ancient homeostatic mechanism in multi-cellular organisms, potentially serving as a steppingstone for the evolution of excitable tissues and neuronal mechano-sensing. The breakdown of membrane potential mediated homeostatic regulation may contribute to tumor growth.

Homeostasis of cytoplasmic crowding by cell wall fluidization and ribosomal counterions

“…No ne-tuned regulation of ion transport is required in this picture. Applying a previously formulated electro-osmotic model of the cytoplasm 32 , we wanted to test if bacteria could achieve scaling of turgor pressure proportional to ribosomes, across a range of different osmolarities of the medium (Box 2B). Indeed, assuming constant active import of potassium and active export of all other inorganic ions (Box 2B), based on observed intracellular concentrations in E. coli 13 , we found a large parameter regime where substantial turgor pressure is generated by ribosomal RNA, which is modulated with changing growth rates via the proteome fraction of ribosomal RNA (Box 2C).…”