UC San Diego

Photoactivatable neurotransmitters provide spatiotemporally precise experimenter control over endogenous receptor activation in living tissue. The resulting optical stimulus-neuronal response relationship provides a sensitive assay that can drive quantitative studies into receptor signaling. Here, we report a photocaged derivative of the prominent catecholamine neurotransmitter noradrenaline (NA). Appending a carboxynitroveratryl (CNV) caging group to the 4-hydroxyl of the catechol group produced CNV-NA, which displays good aqueous solubility and chemical stability. We verified CNV-NA's lack of activity at α_1B- and β₂-adrenoreceptors expressed in HEK cells using a live-cell cAMP assay. We validated CNV-NA photoactivation at native α₂-adrenoreceptors in brain slices of rat locus coeruleus using whole cell electrophysiological recordings. Monitoring the stereotyped outward current response to repeated CNV-NA photoactivation revealed that the neuropeptide substance P suppresses α₂-adrenoreceptor signaling in locus coeruleus neurons. This work adds a new reagent to the growing library of photocaged neuroactive ligands, thereby expanding the scope and applications of photopharmacology.