Reversible Control of Native GluN2B-Containing NMDA Receptors with Visible Light

NMDA receptors (NMDARs)
are glutamate-gated ion channels playing
a central role in synaptic transmission and plasticity. NMDAR dysregulation
is linked to various neuropsychiatric disorders. This is particularly
true for GluN2B-containing NMDARs (GluN2B-NMDARs), which have major
pro-cognitive, but also pro-excitotoxic roles, although their exact
involvement in these processes remains debated. Traditional GluN2B-selective
antagonists suffer from slow and irreversible effects, limiting their
use in native tissues. We therefore developed OptoNAM-3, a photoswitchable
negative allosteric modulator selective for GluN2B-NMDARs. OptoNAM-3
provided light-induced reversible inhibition of GluN2B-NMDAR activity
with precise temporal control both in vitro and in vivo on the behavior
of freely moving Xenopus tadpoles.
When bound to GluN2B-NMDARs, OptoNAM-3 displayed remarkable red-shifting
of its photoswitching properties allowing the use of blue light instead
of UV light to turn-off its activity, which we attributed to geometric
constraints imposed by the binding site onto the azobenzene moiety
of the ligand. This study therefore highlights the importance of the
binding site in shaping the photochemical properties of azobenzene-based
photoswitches. In addition, by enabling selective, fast, and reversible
photocontrol of native GluN2B-NMDARs with in vivo compatible photochemical
properties (visible light), OptoNAM-3 should be a useful tool for
the investigation of the GluN2B-NMDAR physiology in native tissues.