A novel 5-HT2A receptor-linked signalling pathway involving NAADP-mediated lysosomal Ca2+ release

Currently there is major research interest in the therapeutic potential of serotonergic psychedelic drugs across a range of neuropsychiatric disorders1-3. Such drugs exert psychedelic and neuroplastic effects, both likely linked to therapeutic outcomes, via agonist action at the 5-HT2A receptor4-7. This receptor is assumed to generate downstream intracellular signalling via an interaction with either Gq protein coupling and formation of the second messenger inositol trisphosphate (IP3), or through triggering the effector {beta}-arrestin2. Central to the IP3 pathway is mobilisation of Ca2+ stored in the endoplasmic reticulum (ER). Here, we report the unexpected discovery that the 5-HT2A receptor also signals via an additional second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), which mobilises Ca2+ release from lysosomal stores. This effect was revealed through measurement of changes in cellular NAADP levels, pharmacological inhibition of NAADP and direct biosensor measurement of lysosomal Ca2+ release and was produced not only by 5-HT but also by a range of psychedelic drugs in a receptor-specific manner. Moreover, genetic ablation of the NAADP pathway reduced markers of both hallucinogenic and neuroplastic effects of psychedelic drug administration in mouse models. These findings reveal the involvement of a novel, therapeutically relevant signalling pathway in psychedelic drug action.