Mechanosensitive channel activation by diffusio-osmotic force
For ion channel gating, the appearance of two distinct conformational
states and the discrete transitions between them is essential, and
therefore of crucial importance to all living organisms.
Solving the nonequilibrium Stokes-Poisson-Nernst-Planck equations, we
show that a two-state system arises naturally from the diffusio-osmotic
stress caused by the ions and water inside the channel and the elastic
restoring force from the membrane.
Maintaining the balance beteen osmotic and hydrostatic pressure across their cell membranes presents a challenge for organisms when the osmolarity of the environment changes. As a final resort in case of severe osmotic downshock, many unicellular organisms avert cell lysis by activating so-called mechanosensitive membrane channels to release solutes from the cytoplasm. We study this type of membrane channel as a prime example of a large non-selective aqueous ion channel. Although the first crystal structures of mechanosensitive channels have been determined over a decade ago, the physical mechanism by which they sense an osmotic downshock and respond to it remains largely unknown.
We solve the continuum electrokinetic equations, modified to include a molecular potential of mean force in the channel's constriction, in a crystal-structure-based model consisting of a charged vestibule connected to a hydrophobic constriction (Fig. 1). We find that the tension on the channel wall results from a competition between contractile forces due to the ionic potential of mean force and the elastic membrane and expansile forces due to the charged vestibule. The striking result of this competition is that the nonequilibrium free energy landscape exhibits two minima, corresponding to the closed and open states. The two-state energy profile, including a first order phase transition in response to osmotic downshock, emerges directly from the electrokinetic transport equations [1].
Maintaining the balance beteen osmotic and hydrostatic pressure across their cell membranes presents a challenge for organisms when the osmolarity of the environment changes. As a final resort in case of severe osmotic downshock, many unicellular organisms avert cell lysis by activating so-called mechanosensitive membrane channels to release solutes from the cytoplasm. We study this type of membrane channel as a prime example of a large non-selective aqueous ion channel. Although the first crystal structures of mechanosensitive channels have been determined over a decade ago, the physical mechanism by which they sense an osmotic downshock and respond to it remains largely unknown.
We solve the continuum electrokinetic equations, modified to include a molecular potential of mean force in the channel's constriction, in a crystal-structure-based model consisting of a charged vestibule connected to a hydrophobic constriction (Fig. 1). We find that the tension on the channel wall results from a competition between contractile forces due to the ionic potential of mean force and the elastic membrane and expansile forces due to the charged vestibule. The striking result of this competition is that the nonequilibrium free energy landscape exhibits two minima, corresponding to the closed and open states. The two-state energy profile, including a first order phase transition in response to osmotic downshock, emerges directly from the electrokinetic transport equations [1].
Fig. 1.
For small radii, ions are excluded from the stem area, leading to a
contractile net force under isotonic conditions at R = 1.0 nm (1).
After hypotonic shock, the increased electrostatic pressure diminishes
the net force (2).
At R = 1.5 nm, ions enter the hydrophobic constriction and the channel
activates under influence of the expansile electrostatic pressure (3).
This novel modelling scheme reveals the underlying physics of the
channel's complex biological function, showing that the gating kinetics
can be fully reproduced within a model consisting of only a charged
vestibule and a hydrophobic constriction.
Because these elements are shared features of many different ion
channels, our proposed mechanism to produce a two-state gating system is
likely to be important for a broad range of ion channels. Moreover, the
physical insight into the gating mechanism can serve to guide the
design of artificial mechanosensitive ion channels.
| [1] | D. J. Bonthuis and R. Golestanian; Mechanosensitive channel activation by diffusio-osmotic force; Phys. Rev. Lett. 113, 148101 (2014). |