Reimagining biogenic amine signaling in the brain and beyond

Monoaminergic neurotransmission has long been recognized as essential for the development, maintenance, and plasticity of the nervous system, with classical models defining serotonin, dopamine, and histamine as extracellular messengers acting through cell surface receptors. Broadening this view, emerging evidence reveals that biogenic amines also covalently modify proteins, a process termed 'monoaminylation', to directly influence intracellular signaling. The discovery of non-canonical monoamine signaling across subcellular compartments offers new insights into brain-body communication. Here, we review the evolving signaling landscape of protein monoaminylations and highlight new chemical-biological tools for probing their impact on neural development, plasticity, and disease.