Photoswitchable Amino Acids For Control Of NMDA Receptor Activity

Nerve cells communicate with each other by releasing chemicals, known as neurotransmitters, from one cell to the next. Once released, these neurotransmitters bind to specific docking stations, called receptors, which are located on the surface of the neighboring cell.

Due to changes in neurotransmitter release or the receptor number, the connections between neurons can either strengthen or weaken over time. This process, called synaptic plasticity, forms the basis of learning and memory. One of the key players in synaptic plasticity are N-methyl-D-aspartate (NMDA) receptors, and if these receptors are faulty, it can cause disorders such as schizophrenia or epilepsy.

NMDAs are a large family of receptors that have many receptor subtypes, each with specific properties. Every subtype is composed of four varying subunits. It is still unclear how these different receptor subtypes contribute to synaptic plasticity and new methods are needed to resolve this puzzle.

Light Switch Molecule

An emerging strategy to study brain receptors, known as optogenetics, is to engineer them so that they can be controlled with light. One approach to provide light-sensitivity uses molecules that act as ‘light switches’.

These switches change their shape when exposed to specific colors of light and this way, turn a receptor on or off. However, commonly used light switches are often very large, meaning that they can only be introduced at specific sites in a receptor, and have limited ability to change the shape of a receptor.

Proposed mechanism for photomodulation of the gating and permeation properties of NMDARs carrying PSAAs.
(a) Toggling of the PSAA azobenzene moiety between the trans- and cis-isomers in dependence of blue or UV light. For simplicity, the two isomers are replaced by symbols as indicated.
(b) Schematic representation of the mechanism underlying the photomodulation at the ABD level. For clarity, only one dimer is represented and the NTD region is omitted. PSAA in its…

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