Environmental stresses and clinical drugs paralyze a cell

Abstract

Cells respond and adapt to various extracellular changes. Environmental stresses, such as high osmolarity and acute glucose deprivation, rapidly and transiently shut down translation initiation and actin polarization in the yeast Saccharomyces cerevisiae. Certain clinical drugs, such as local anesthetics and antipsychotic phenothiazines, and cationic surfactants also cause shutdowns similar to those triggered by environmental stresses. These compounds all have an amphiphilic structure, a cationic hydrophilic region, surfactant activity, and the ability to lyse yeast cells. Since low concentrations of these compounds shut down intracellular reactions in the absence of cell lysis, the compounds might change the state of the cell's membrane by intercalating into the membrane and thus generate signals for the shutdown, as do environmental stresses. The intracellular shutdowns caused by stresses might essentially be the same as the paralysis caused by clinical drugs at the cellular level.

Keywords: actin; anesthetic; phenothiazine; stress; surfactant; translation; yeast.

Figure 1

Transient shutdown in response to environmental stresses. The intracellular reaction in budding yeast upon exposure to stress, such as high osmolarity or glucose deprivation, is separated into three steps: the normal situation before exposure to stress, the shutdown phase just after exposure to stress, and the adaptation phase in the continued presence of the stress.

Figure 2

The structures of compounds eliciting intracellular shutdowns. The structures of a local anesthetic, a phenothiazine, a cationic surfactant, and an anionic surfactant are shown. TC, CPZ, BC and SDS indicate tetracaine, chlorpromazine, benzethonium chloride, sodium dodecyl sulfate, respectively.

Figure 3

A model for shutdown via membrane perturbation induced by drug or environmental stress. (A) The outer leaflet of the plasma membrane is perturbed by low concentrations of anionic surfactants, but is disrupted at high concentrations, whereas the leaflet is transiently perturbed by mild heat stress. During either perturbation, a putative signal for shutdown of both actin polarization and cytoplasmic retention of Msn2 is generated. (B) Inner or both leaflets of the membrane are perturbed by low concentrations of cationic surfactants, local anesthetics or phenothiazines, but are disrupted by high concentrations, whereas the leaflets are transiently perturbed by osmotic stress or glucose deprivation. These perturbations generate a signal for shutdown of translation initiation and actin polarization, and bring about the rapid nuclear localization of Msn2.