Ultra light-sensitive and fast light switch for nerve cells
The use of a highly light-sensitive membrane protein enables precise control of nerve cell activity with weak light stimuli.
Whether in worms, flies or mice – scientists can now control nerve cells using light pulses and thereby even control their behaviour. The basis for the research area of optogenetics is light-sensitive membrane proteins – channelrhodopsins – which can be inserted into cell membranes. When exposed to light, these proteins trigger a nerve impulse. Researchers at the Max-Planck-Institute for Biophysics in Frankfurt have now developed a novel, ultra light-sensitive channelrhodopsin. Thanks to its slightly increased calcium permeability, the protein variant CatCh (calcium translocating channelrhodopsin) can trigger nerve impulses with 70-fold less light and greater precision and speed than other forms of the protein. This allows for the light stimulation of cells located in deeper brain regions without the need for additional optic fibres. Moreover, sunlight can be used instead of laser light to simulate the cells. Thus, the new molecule presents a promising tool for possible use in clinical applications to treat individuals suffering from diseases like epilepsy, Parkinson’s or blindness.
Nerve cells that can be switched on and off using blue light pulses – what sounds like science fiction has become reality over the last few years. The new research area of optogenetics uses light to control the activity of cells. For this scientists deliver a gene into the cell’s genetic material; this gene contains the building instructions for an ultra light-sensitive channel protein in the cell membrane – channelrhodopsin. When such a biotechnologically modified nerve cell is exposed to blue light, positively charged ions flow through the channel protein into the cell so that the cell’s interior becomes positively charged, thereby triggering an electrical signal.
A research group led by Ernst Bamberg at the Max-Planck-Institute for Biophysics in Frankfurt has now developed a new, ultra light-sensitive channelrhodopsin. Nerve cells containing the mutant CatCh (calcium translocating channelrhodopsin) have a 70-fold higher sensitivity to light than cells containing the natural form of the protein. Due to its permeability for positively charged calcium ions CatCh also exhibits a much shorter response time and can therefore respond faster to light stimuli.
"CatCh opens up a whole palette of new possibilities thanks to its high sensitivity to light," says Sonja Kleinlogel, first author of the publication. "It allows us to control cells located in deeper brain regions without the need to transmit the light pulse to these areas using optic fibres. Moreover, the possibility to use longer wavelengths of light or reducing the light power to activate CatCh prevents tissue damage, which is an issue when stimulating other channelrhodopsins with strong laser light." Thanks to its fast response kinetics the new channelrhodopsin also enables the control of cells that intrinsically fire at higher frequencies, such as the hair cells in the inner ear or some interneurons in the cortex. This combination of high light-sensitivity with a fast response time is unique and does not exist in any other variant of the channelrhodopsin protein.
Channelrhodopsin was originally isolated from the unicellular green algae Chlamydomonas rheinhardtii. As a component of their cell wall, it enables the algae to respond to light. Since its discovery in 2003, also in Ernst Bamberg’s research group at the MPI for Biophysics, the channelrhodopsins have become an important tool in cell and neurobiology and have revolutionised brain research. For the first time, nerve cells can be controlled without the use of electrodes and this with unmatched temporal and spatial precision. Thus the molecular activity-switches are not only indispensable tools to unravel the functional connectivity of the brain, but also bear a huge potential for future clinical, genetherapeutic applications.
For example, they could be used to treat blindness caused by the loss of photoreceptors. Patients with diseases such as epilepsy or Parkinson’s may also profit from these “light switches”. "Normal sunlight already suffices to activate CatCh and thus excite nerve cells," says Sonja Kleinlogel. "The event of CatCh moved optogenetics a big step forward into direction of clinical treatments".