Polyamines are regulatory metabolites that play crucial roles in transcription, translation, cell signaling, and autophagy. They are involved in various neurological disorders, including stroke, epilepsy, and neurodegeneration, and can modulate neuronal excitability by interacting with ion channels. Polyamines have also been linked to pain, with altered levels observed in persistent pain conditions in humans and changes in pain behavior in animal models. However, the mechanisms controlling polyamine transport in the nervous system remain unclear. In a genome-wide association study (GWAS) of chronic pain intensity within the UK Biobank, we identified significant associations with variants located in the SLC45A4 gene locus. In the mouse nervous system, SLC45A4 expression is enriched across all sensory neuron subtypes within the dorsal root ganglion, including nociceptors. Cell-based assays reveal that SLC45A4 functions as a selective plasma membrane transporter of polyamines, while the cryo-EM structure, in complex with polyamines and toxins, uncovers a novel regulatory domain and provides insight into polyamine recognition. Mice lacking SLC45A4 exhibit normal mechanosensitivity but show reduced sensitivity to noxious heat and algogen-induced tonic pain, correlating with decreased excitability of C-polymodal nociceptors. Our findings thus demonstrate a role for neuronal polyamine transport in pain perception and highlight a potential new target for therapeutic intervention in pain management.
Newstead et al. (Sun,) studied this question.