Mechanisms for sensing force

Mechanosensation refers to the mechanisms of mechanical stimuli, which are responsible for sensations through of our five senses. Dr Armagan Kocer of the Mechanosensation project has set out to study what the molecular mechanisms of mechanosensation are..

Unlike sight, taste and smell, the functioning of the sensations of touch and hearing at a molecular level are currently unknown. Sensing mechanical force is something that all organisms have in common, and the Mechanosensation project is now investigating the Mechanosensitive (MS) ion channels in membranes, the molecules that sense membrane tension in all species. The process is different from sensing a chemical compound, in which a receptor in the cell recognises a specific chemical compound like a ‘key-lock’ relationship and triggers a signal. However, there are no dissolved ligands involved in sensing mechanosensation – simply organisms sensing the force. This mechanism, prevalent throughout nature, makes it significant and important.

“Many other basic concepts of life, for example the genetic code and its expression, were also first worked on with microorganisms and only later were found to be universal,” explains Dr Armagan Koçer, whose research explores the long-standing question of how MscL, ‘the simplest’ version of a mechanosensitive channel, senses tension. “[The research] will also shed light on the common property of mechanosensitivity among nature’s sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions. It will bring us closer to answer the question asked by Ching Kung (Nature Vol. 436, 647-654, 2005) ‘is there a common basis that determines how channel proteins sense force, which may serve to unite the varied biological manifestations’”.

The project aims to understand how channel proteins sense mechanical force at a molecular level. The chosen bacterial channel, MscL, is one of the best-characterised mechanosensitive channel proteins. It can naturally keep its mechanosensitivity intact in artificial lipid bilayers, implying that no other component for sensing mechanical force in the membrane is needed. It also couples the tension in the lipid bilayer to the protein conformation, making it possible to follow structural changes upon channel activation by using different spectroscopic techniques.



Structural models of MscL and its gating mechanism suggests that the channel undergoes dramatic conformational changes in order to go from a 2 Å closed to a 35 Å open state upon mechano-sensation. Experimental changes in the channel structure and energetics have been followed as changes in ion flow through the open channel pore by using the patch clamp technique. This technique allows applying suction to the patched membrane, which mimics the tension in the membrane. At the same time, it allows measuring the ions flowing through the open channels.



Dr Koçer’s research however, asserts that the mechanism is already actively sensing prior to the channel opening. “It has been proposed,” states Koçer, “and supported also by my own data that, before the point of channel opening, the channel has already undergone dramatic structural changes. At this stage, open form, MscL must already have sensed the mechanical force, and passed the major energy barrier required for the opening. Therefore the very first events upon tension in the membrane reflects how the channel senses the mechanical force, and therefore are important to understand.”

The Mechanosensation project, based on previous studies of the MscL channel by Dr Koçer at the Biomade Technology Foundation, lasts for five years. Koçer has two PhD students working full time on the project, but will soon require additional resources. Already, the project has gained control of the channel function in a reversible way, for the first time. “It gives us full control over manipulating the channel activity,” explains Koçer. “We can activate the channel and follow the structural changes and after that we can revert it to its inactive form without re-engineering it. We can repeat this cycle with the same sample multiple times. And now even better than this, with our recent finding we can activate individual subunits, one at a time in a reversible manner and record structural changes back and forth as we like.”

“We obtained a single subunit resolution for a homopentamer protein by converting into a functional heteropentamer with individually addressable subunits. While doing that we managed to stay as close to its natural form as possible.”

The project gives researchers an insight into how the system works which could in turn have relevance to understanding human diseases and even lead to the design of new drugs to fight them. “On the fundamental dimension, by combining the forces of chemistry and biology we will be able to go beyond today’s limits on mechanosensation research,” confirms Dr Koçer.

The project has overcome technical limitations, developing their own tools to use spectroscopy while mimicking membrane tension in a controlled way to obtain information. The next step is to apply their findings to mechanosensitive channels from higher organisms, such as TRP channels.

“[T]he engineering power that we have on this protein allows us to use it as a remote-controlled nano-valve in sensory and delivery devices,” says Dr Koçer. This part of the work has being supported by two EU projects, MEDITRANS (KP6) and BISNES (FP7) and a national funding NanoNED (a Dutch nanotechnology R&D initiative) and there are three international patents on possible uses of this engineered channel.

For more information on the project, contact Dr Armagan Koçer at a.kocer@rug.nl

Published: Monday, 19th January 2009 by Tom Freeman

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