Cell shape regulates subcellular organelle location to control short-term Ca2+ signal dynamics in VSMC

ABSTRACT The shape of the cell is intimately connected to its function; however, we do not fully understand the underlying mechanism by which global shape regulates cell function. Here, using a combination of theory, experiments and simulation, we investigated how global cell shape can affect subcellular organization, and consequently intracellular signaling, to control information flow needed for phenotypic function. We find that global cell curvature regulates the location of the sarcoplasmic reticulum, inter-organelle distances and differential distribution of receptors in the plasma membrane. A combination of these factors leads to the modulation of signals transduced by the M3 muscarinic receptor/Gq/PLCβ pathway at the plasma membrane, amplifying Ca2+ dynamics in the cytoplasm and the nucleus resulting in phenotypic changes, as determined by increased activity of myosin light chain kinase in the cytoplasm and enhanced nuclear localization of the transcription factor NFAT. Taken together, our observations show a systems level phenomenon whereby global cell shape affects subcellular organization and signaling to enable phenotypic changes. One Sentence Summary The physical interplay of the curvature of the plasma membrane and global cell shape alters the distances between subcellular organelles, which in turn modulates the strength of Ca2+ signaling in vascular smooth muscle cells.