Cooperative response and clustering: Consequences of membrane-mediated interactions among mechanosensitive channels

Abstract

Mechanosensitive (MS) channels are ion channels which act as cells' safety valves, opening when the osmotic pressure becomes too high and making cells avoid damage by releasing ions. They are found on the cellular membrane of a large number of organisms. They interact with each other by means of deformations they induce in the membrane. We show that collective dynamics arising from the inter-channel interactions lead to first and second-order phase transitions in the fraction of open channels in equilibrium relating to the formation of channel clusters. We show that this results in a considerable delay of the response of cells to osmotic shocks, and to an extreme cell-to-cell stochastic variations in their response times, despite the large numbers of channels present in each cell. We discuss how our results are relevant for E. coli.Abrupt changes in the osmolarity of the environment is a hazard most organisms are subject to at one time or another [1][2][3][4][5][6]. A sudden drop in osmolarity (an osmotic shock ) will cause water to rush into a living cell, and requires an immediate response by the cell to prevent it from getting damaged or undergoing lysis from the increased tension on the cellular membrane. Mechanosensitive channels (or MS channels) are ion channels located on the cell membrane, which open when the membrane tension becomes too high [7,8], and play a crucial role in the cell's defence mechanism against osmotic shocks [9,10]. They act as safety valves, releasing ions and decreasing the osmotic pressure and the membrane tension. Mechanosensitive channels are found in many organisms, and have been well characterised in the bacterium E. coli [11-13].The cellular membrane in which the mechanosensitive channels are inserted is a lipid bilayer. The interior of the bilayer is hydrophobic, making it energetically favourable for it to thicken or compress to match the hydrophobic parts of the channel proteins inserted in the membrane [14]. This results in a deformation profile around each channel, with the thickness of the bilayer being a function of position. This deformation mediates a shortrange effective force between two neighbouring channels, similar to the force between two nearby corks floating on water, which interact through the deformation they induce on the surface of water. This interaction can be attractive or repulsive, depending on the shapes of the two molecules. Furthermore, a theoretical analysis suggests that the interaction between two neighbouring channels lowers the tension needed to open them during an osmotic shock [15], raising the possibility that their function could be influenced by their spatial distribution on the membrane (as already noticed for other membrane proteins [16,17]). This is reinforced by the fact that the channels' attractive forces suggest that they may agglomerate into clusters. Our goal in this paper is to determine the consequences that the inter-channel interaction has on the dynamics of this system, focusing in particular on channel clustering and its con...

Dynamic Clustering Regulates Activity of Mechanosensitive Membrane Channels

“…Previous continuum models suggested that, due to hydrophobic mismatch, membrane-mediated interactions between rigid, cylindrically symmetric, MSCs will lead to their collective opening [41][42][43]. This is not what we observe.…”