Biology subjects

Rangamani, P.

Publications and source records attributed to Rangamani, P..

95 records · Page 6Linked to original sources

bioRxiv2018

Solubilization kinetics determines the pulsatory dynamics of lipid vesicles exposed to surfactant

We establish a biophysical model for the dynamics of lipid vesicles exposed to surfactants. The solubilization of the lipid membrane due to the insertion of surfactant molecules induces a reduction of membrane surface area at almost constant vesicle volume. This results in a rate-dependent increase of membrane tension and leads to the opening of a micron-sized pore. We show that solubilization kinetics due to surfactants can determine the regimes of pore dynamics: either the pores open and reseal within a second (short-lived pore), or the pore stays open up to a few minutes (long-lived pore). First, we validate our model with previously published experimental measurements of pore dynamics. Then, we investigate how the solubilization kinetics and membrane properties affect the dynamics of the pore and construct a phase diagram for short and long-lived pores. Finally, we examine the dynamics of sequential pore openings and show that cyclic short-lived pores occur at a period inversely proportional to the solubilization rate. By deriving a theoretical expression for the cycle period, we provide an analytic tool to measure the solubilization rate of lipid vesicles by surfactants. Our findings shed light on some fundamental biophysical mechanisms that allow simple cell-like structures to sustain their integrity against environmental stresses, and have the potential to aid the design of vesicle-based drug delivery systems.

biophysics↗

bioRxiv2017

Curvature regulates subcellular organelle location to control intracellular signal propagation

The shape of the cell is connected to its function; however, we do not fully understand underlying mechanisms by which global shape regulates a cells 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/PLC{beta} 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.

cell biology↗

bioRxiv2017

The role of traction in membrane curvature generation

Curvature of biological membranes can be generated by a variety of molecular mechanisms including protein scaffolding, compositional heterogeneity, and cytoskeletal forces. These mechanisms have the net effect of generating tractions (force per unit length) on the bilayer that are translated into distinct shapes of the membrane. Here, we demonstrate how the local shape of the membrane can be used to infer the traction acting locally on the membrane. We show that buds and tubes, two common membrane deformations studied in trafficking processes, have different traction distributions along the membrane and that these tractions are specific to the molecular mechanism used to generate these shapes. Furthermore, we show that the magnitude of an axial force applied to the membrane as well as that of an effective line tension can be calculated from these tractions. Finally, we consider the sensitivity of these quantities with respect to uncertainties in material properties and follow with a discussion on sources of uncertainty in membrane shape.

biophysics↗

bioRxiv2017

Guanine-nucleotide Exchange Modulator, GIV/Girdin, Serves as a Tunable Valve for Growth Factor-Stimulated Cyclic AMP Signals

Cellular levels of the versatile second messenger, cyclic-(c)AMP are regulated by the antagonistic actions of the canonical G protein[->]adenylyl cyclase pathway that is initiated by G-protein-coupled receptors (GPCRs) and by phosphodiesterases (PDEs); dysregulated cAMP signaling drives many diseases, including cancers. Recently, an alternative paradigm for cAMP signaling has emerged, in which growth factor-receptor tyrosine kinases (RTKs; e.g., EGFR) access and modulate G proteins via cytosolic guanine-nucleotide exchange modulator (GEM), GIV/Girdin; dysregulation of this pathway is frequently encountered in cancers. Here we present a comprehensive network-based compartmental model for the paradigm of GEM-dependent signaling that reveals unforeseen crosstalk and network dynamics between upstream events and the various feedback-loops that fine-tune the GEM action of GIV, and captures the experimentally determined dynamics of cAMP. The model also reveals that GIV acts a tunable control-valve within the RTK[->]cAMP pathway; hence, it modulates cAMP via mechanisms distinct from the two most-often targeted classes of cAMP modulators, GPCRs and PDEs.

systems biology↗

bioRxiv2017

Gaussian Curvature Directs The Distribution Of Spontaneous Curvature On Bilayer Membrane Necks

Formation of membrane necks is crucial for fission and fusion in lipid bilayers. In this work, we seek to answer the following fundamental question: what is the relationship between protein-induced spontaneous mean curvature and the Gaussian curvature at a membrane neck? Using an augmented Helfrich model for lipid bilayers to include membrane-protein interaction, we solve the shape equation on catenoids to find the field of spontaneous curvature that satisfies mechanical equilibrium of membrane necks. In this case, the shape equation reduces to a variable coefficient Helmholtz equation for spontaneous curvature, where the source term is proportional to the Gaussian curvature. We show how this latter quantity is responsible for non-uniform distribution of spontaneous curvature in minimal surfaces. We then explore the energetics of catenoids with different spontaneous curvature boundary conditions and geometric asymmetries to show how heterogeneities in spontaneous curvature distribution can couple with Gaussian curvature to result in membrane necks of different geometries.

biophysics↗