Abstract
The shape of the cell is connected to its function; however, we do not fully understand underlying mechanisms by which global shape regulates a cell’s functional capabilities. Using theory, experiments and simulation, we investigated how physiologically relevant cell shape changes affect subcellular organization, and consequently intracellular signaling, to control information flow needed for phenotypic function. Vascular smooth muscle cells going from a proliferative and motile circular shape to a contractile fusiform shape show changes in the location of the sarcoplasmic reticulum, inter-organelle distances, and differential distribution of receptors in the plasma membrane. These factors together lead 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 to modulate signaling that enables phenotypic changes.
Highlights
The shape of the cell is connected to its function; we do not fully understand underlying mechanisms by which global shape regulates a cell’s functional capabilities
In vascular smooth muscle cells (VSMC), C a2+ regulates both contractility and gene expression through IP3-mediated Ca2+ release by IP3R receptors located on the membrane of the sarcoplasmic reticulum (SR) and through Ca2+ influx at the plasma membrane14–16. Ca2+-calmodulin activates myosin light chain kinase (MLCK), which phosphorylates the light chain of myosin, initiating contraction17. Ca2+ activates protein kinases and phosphatases that regulate transcription regulators that define the phenotypic status of VSMC18. Ca2+ activates calcineurin, which dephosphorylates the transcription factor nuclear factor of activated T-cells (NFAT) in the cytoplasm, resulting in its nuclear accumulation and
A signaling molecule of interest, C A, is produced at the PM with an on-rate kon and binds to a receptor located at the SR membrane, with a rate koff and is free to diffuse in the sandwiched cytoplasmic space and is degraded by a degrading enzyme with a rate kdeg (1/s)
Summary
The shape of the cell is connected to its function; we do not fully understand underlying mechanisms by which global shape regulates a cell’s functional capabilities. Vascular smooth muscle cells going from a proliferative and motile circular shape to a contractile fusiform shape show changes in the location of the sarcoplasmic reticulum, interorganelle distances, and differential distribution of receptors in the plasma membrane These factors together lead 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. Based on the observations that cell shape and Ca2+ signaling closely regulate the contractile phenotype of differentiated VSMCs, we hypothesized that cell shape regulates organelle location, including the relative distances between plasma membrane, endoplasmic/sarcoplasmic reticulum (ER/SR) and the nucleus, to modulate cellular functions. We tested the effect of cell shape on VSMC contractility and found an unexpected modulation of organelle location as a function of cell shape and that this change in organelle location results in signal amplification in the cytoplasm and nucleus
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
