A novel 5-HT 2A receptor-linked signalling pathway involving NAADP-mediated lysosomal Ca 2+ release

Currently there is major research interest in the therapeutic potential of serotonergic psychedelic drugs across a range of neuropsychiatric disorders 1-3 . Such drugs exert psychedelic and neuroplastic effects, both likely linked to therapeutic outcomes, via agonist action at the 5-HT 2A receptor 4-7 . This receptor is assumed to generate downstream intracellular signalling via an interaction with either G q protein coupling and formation of the second messenger inositol trisphosphate (IP 3 ), or through triggering the effector β-arrestin2. Central to the IP 3 pathway is mobilisation of Ca 2+ stored in the endoplasmic reticulum (ER). Here, we report the unexpected discovery that the 5-HT 2A receptor also signals via an additional second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), which mobilises Ca 2+ 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 Ca 2+ 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.