Substratum stiffness tunes membrane voltage in mammary epithelial cells

Membrane voltage (V-m) plays a critical role in the regulation of several cellular behaviors, including proliferation, apoptosis and phenotypic plasticity. Many of these behaviors are affected by the stiffness of the underlying extracellular matrix, but the connections between V-m and the mechanical properties of the microenvironment are unclear. Here, we investigated the relationship between matrix stiffness and V-m by culturing mammary epithelial cells on synthetic substrata, the stiffnesses ofwhichmimicked those of the normalmammary gland and breast tumors. Although proliferation is associated with depolarization, we surprisingly observed that cells are hyperpolarized when cultured on stiff substrata, a microenvironmental condition that enhances proliferation. Accordingly, we found that V-m becomes depolarized as stiffness decreases, in a manner dependent on intracellular Ca2+. Furthermore, inhibiting Ca2+-gated Cl- currents attenuates the effects of substratum stiffness on V-m. Specifically, we uncovered a role for cystic fibrosis transmembrane conductance regulator (CFTR) in the regulation of V-m by substratum stiffness. Taken together, these results suggest a novel role for CFTR and membrane voltage in the response of mammary epithelial cells to their mechanical microenvironment.

Automated summary

Membrane voltage plays a critical role in regulating cellular behaviors such as proliferation, apoptosis, and phenotypic plasticity. The stiffness of the extracellular matrix influences membrane voltage, and a decrease in stiffness leads to depolarization of the membrane, affecting cell proliferation. The cystic fibrosis transmembrane conductance regulator (CFTR) has been identified as playing a role in regulating membrane voltage in response to substrate stiffness, suggesting a novel mechanism in cell response to the mechanical microenvironment.