Delving deeper into the inner workings of cells

Research carried out at IBEC has opened the way to new applications to control the activation of neurons and other working parts of cells.

The dream of precisely and remotely controlling every aspect of the cell’s inner workings in tissue offers the promise of uncovering the molecular mechanisms of complex cellular processes, which in turn can lead to leaps in our understanding of what happens when things go wrong – for example, how and when neurodegenerative diseases can develop.

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Image: A hippocampal neuron that has been photosensitized with the novel compounds (left), can be stimulated with a 900 nm pulsed laser to produce a burst of action potentials that can be measured by patch clamp (right)

IBEC’s Nanoprobes and Nanoswitches group and their collaborators in Spain and the USA have published a paper in JACS that outlines a new way to use light-regulated proteins – protein ‘switches’ which, controlled remotely, can turn specific biochemical functions in living cells on or off, thus enabling researchers to set up and test a multitude of scenarios within the cell – to activate or deactivate processes at a much deeper level in tissue, and with higher 3D resolution.

“Photoswitchable biomolecules are used to precisely manipulate cellular biochemical processes, but until now, nobody has explored a microscopy method known as two-photon excitation – which offers deeper tissue penetration, smaller excitation volume, and reduced phototoxicity and photobleaching – in relation to these switches,” explains Pau Gorostiza, head of IBEC’s Nanoprobes and Nanoswitches group and ICREA research professor. “Now, existing protein switches can be also used with multi-photon excitation with near-infrared light, providing subcellular resolution.”

The researchers adjusted the response to light of existing photoswitchable proteins to be adapted to two-photon stimulation technology, and thus were able to obtain control at a single cell and subcellular level, without disturbing the proteins’ normal functional properties, and with much more spatial precision.

This discovery constitutes an important advance in optogenetics and optopharmacology to control and monitor the activities of individual light-sensitized neurons in order to be able to map neural circuits.

Reference article: Izquierdo-Serra M, Gascón-Moya M, Hirtz JJ, Pittolo S, Poskanzer KE, Ferrer E, Alibés R, Busqué F, Yuste R, Hernando J, Gorostiza P. (2014). Two-Photon Neuronal and Astrocytic Stimulation with Azobenzene-Based Photoswitches. J Am Chem Soc. 2014 Jun 18;136(24):8693-701