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SLC45A4 is a pain gene encoding a neuronal polyamine transporter.
Steven J Middleton1, Sigurbjörn Markússon2,3, Mikael Åkerlund4
1Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK.
Nature
|August 20, 2025
Summary
Scientists identified SLC45A4 as a key gene influencing chronic pain intensity. This gene encodes a polyamine transporter in sensory neurons, crucial for pain perception and a potential target for pain therapeutics.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Polyamines are vital metabolites involved in cellular processes and neurological functions.
- Altered polyamine levels are linked to neurological disorders and pain states.
- The mechanisms of polyamine transport in the nervous system are not well understood.
Purpose of the Study:
- To investigate the genetic basis of chronic pain intensity.
- To identify novel genes and pathways involved in pain perception.
- To explore the role of polyamine transport in neuronal function and pain.
Main Methods:
- Genome-wide association study (GWAS) of chronic pain in UK Biobank participants.
- Analysis of Slc45a4 gene expression in mouse sensory neurons.
- Cell-based assays and cryo-electron microscopy (cryo-EM) to characterize SLC45A4 function and structure.
- Phenotypic analysis of Slc45a4 knockout mice for sensory and pain behaviors.
Main Results:
- GWAS identified a significant association between chronic pain intensity and the SLC45A4 gene locus.
- Slc45a4 is highly expressed in sensory neurons, including nociceptors, in the mouse nervous system.
- SLC45A4 functions as a selective plasma membrane polyamine transporter.
- Slc45a4 knockout mice exhibit reduced sensitivity to heat and algogen-induced pain, linked to decreased C-polymodal nociceptor excitability.
Conclusions:
- Neuronal polyamine transport mediated by SLC45A4 plays a critical role in pain perception.
- SLC45A4 is a novel molecular target for therapeutic interventions in pain management.
- Understanding polyamine transport systems offers new avenues for treating pain disorders.
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