SLC45A4 is a pain gene encoding a neuronal polyamine transporter

Steven J Middleton^#¹, Sigurbjörn Markússon^#^{2

3}, Mikael Åkerlund⁴, Justin C Deme⁵, Mandy Tseng¹, Wenqianglong Li¹, Sana R Zuberi¹, Gabriel Kuteyi^{2

3}, Peter Sarkies², Georgios Baskozos¹, Jimena Perez-Sanchez¹, Adham Farah¹, Harry L Hébert⁶, Sylvanus Toikumo^{7

8}, Zhanru Yu^{9

10}, Susan Maxwell¹, Yin Y Dong¹, Benedikt M Kessler^{9

10}, Henry R Kranzler^{7

8}, John E Linley¹¹, Blair H Smith⁶, Susan M Lea⁵, Joanne L Parker^{2

3}, Valeriya Lyssenko^{4

12

13}, Simon Newstead^#^{14

15}, David L Bennett^#¹⁶

Affiliations

¹ Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK.
² Department of Biochemistry, University of Oxford, Oxford, UK.
³ The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
⁴ Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Lund, Sweden.
⁵ Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
⁶ Chronic Pain Research Group, Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁷ Mental Illness Research, Education and Clinical Center, Crescenz VA Medical Center, Philadelphia, PA, USA.
⁸ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
¹⁰ Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹¹ Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹² Department of Clinical Science, University of Bergen, Bergen, Norway.
¹³ Steno Diabetes Center Copenhagen, Herlev, Denmark.
¹⁴ Department of Biochemistry, University of Oxford, Oxford, UK. Simon.newstead@bioch.ox.ac.uk.
¹⁵ The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. Simon.newstead@bioch.ox.ac.uk.
¹⁶ Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK. David.bennett@ndcn.ox.ac.uk.

^# Contributed equally.

PMID: 40836097
DOI: 10.1038/s41586-025-09326-y

SLC45A4 is a pain gene encoding a neuronal polyamine transporter

Steven J Middleton et al. Nature. 2025.

. 2025 Aug 20.

doi: 10.1038/s41586-025-09326-y. Online ahead of print.

Authors

Affiliations

¹ Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK.
² Department of Biochemistry, University of Oxford, Oxford, UK.
³ The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
⁴ Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Lund, Sweden.
⁵ Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
⁶ Chronic Pain Research Group, Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁷ Mental Illness Research, Education and Clinical Center, Crescenz VA Medical Center, Philadelphia, PA, USA.
⁸ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
¹⁰ Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹¹ Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹² Department of Clinical Science, University of Bergen, Bergen, Norway.
¹³ Steno Diabetes Center Copenhagen, Herlev, Denmark.
¹⁴ Department of Biochemistry, University of Oxford, Oxford, UK. Simon.newstead@bioch.ox.ac.uk.
¹⁵ The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. Simon.newstead@bioch.ox.ac.uk.
¹⁶ Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK. David.bennett@ndcn.ox.ac.uk.

^# Contributed equally.

PMID: 40836097
DOI: 10.1038/s41586-025-09326-y

Abstract

Polyamines are regulatory metabolites with key roles in transcription, translation, cell signalling and autophagy¹. They are implicated in multiple neurological disorders, including stroke, epilepsy and neurodegeneration, and can regulate neuronal excitability through interactions with ion channels². Polyamines have been linked to pain, showing altered levels in human persistent pain states and modulation of pain behaviour in animal models³. However, the systems governing polyamine transport within the nervous system remain unclear. Here, undertaking a genome-wide association study (GWAS) of chronic pain intensity in the UK Biobank (UKB), we found a significant association between pain intensity and variants mapping to the SLC45A4 gene locus. In the mouse nervous system, Slc45a4 expression is enriched in all sensory neuron subtypes within the dorsal root ganglion, including nociceptors. Cell-based assays show that SLC45A4 is a selective plasma membrane polyamine transporter, and the cryo-electron microscopy (cryo-EM) structure reveals a regulatory domain and basis for polyamine recognition. Mice lacking SLC45A4 show normal mechanosensitivity but reduced sensitivity to noxious heat- and algogen-induced tonic pain that is associated with reduced excitability of C-polymodal nociceptors. Our findings therefore establish a role for neuronal polyamine transport in pain perception and identify a target for therapeutic intervention in pain treatment.

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Conflict of interest statement

Competing interests: D.L.B. has acted as a consultant for 5AM Ventures, AditumBio, AstraZeneca, Biogen, Biointervene, Combigene, GSK, Ionis, Lexicon Therapeutics, Neuvati, Novo Ventures, Olipass, Orion, Replay, SC Health Managers, Third Rock Ventures, Vida Ventures, Vertexon on behalf of Oxford University Innovation over the past two years. The PAINSTORM consortium received funding from Eli Lilly and AstraZeneca. The DOLORisk consortium received funding from Eli Lilly. J.E.L. is an employee of AstraZeneca. H.R.K. is a member of advisory boards for Altimmune and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals and Altimmune; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past three years by Alkermes, Dicerna, Ethypharm, Imbrium, Indivior, Kinnov, Lilly, Otsuka and Pear Therapeutics; and is listed as an inventor on US provisional patent ‘Multi-ancestry Genome-wide Association Meta-analysis of Buprenorphine Treatment Response’.

References

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SLC45A4 is a pain gene encoding a neuronal polyamine transporter

Affiliations

SLC45A4 is a pain gene encoding a neuronal polyamine transporter

Authors

Affiliations

Abstract

Conflict of interest statement

References