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

5-HT2A receptor activation is linked to NAADP-mediated lysosomal Ca2+ release, revealed by NAADP level changes and lysosomal Ca2+ biosensor readouts.

• Why it matters: The field needs clearer downstream signalling mechanisms for serotonergic psychedelic drugs, beyond the assumed IP3/ER Ca2+ and β-arrestin routes.
• What they did: They measured cellular NAADP changes, used pharmacological NAADP inhibition, and directly biosensed lysosomal Ca2+ release; 5-HT and multiple psychedelic drugs triggered this pathway in a receptor-specific manner.
• The result: In mouse models, genetic ablation of the NAADP pathway reduced markers of both hallucinogenic and neuroplastic effects after psychedelic drug administration, supporting therapeutic relevance.

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