SLC45A4 is a pain gene encoding a neuronal polyamine transporter

Steven J. Middleton, Sigurbjörn Markússon, Mikael Åkerlund, Justin C. Deme, Mandy Tseng, Wenqianglong Li, Sana R. Zuberi, Gabriel Kuteyi, Peter Sarkies, Georgios Baskozos, Jimena Perez-Sanchez, Adham Farah, Harry L. Hébert, Sylvanus Toikumo, Zhanru Yu, Susan Maxwell, Yin Y. Dong, Benedikt M. Kessler, Henry R. Kranzler, John E. Linley, Blair H. Smith, Susan M. Lea, Joanne L. Parker, Valeriya Lyssenko, Simon Newstead () and David L. Bennett ()
Additional contact information
Steven J. Middleton: The University of Oxford
Sigurbjörn Markússon: University of Oxford
Mikael Åkerlund: Lund University
Justin C. Deme: National Cancer Institute
Mandy Tseng: The University of Oxford
Wenqianglong Li: The University of Oxford
Sana R. Zuberi: The University of Oxford
Gabriel Kuteyi: University of Oxford
Peter Sarkies: University of Oxford
Georgios Baskozos: The University of Oxford
Jimena Perez-Sanchez: The University of Oxford
Adham Farah: The University of Oxford
Harry L. Hébert: University of Dundee
Sylvanus Toikumo: Crescenz VA Medical Center
Zhanru Yu: University of Oxford
Susan Maxwell: The University of Oxford
Yin Y. Dong: The University of Oxford
Benedikt M. Kessler: University of Oxford
Henry R. Kranzler: Crescenz VA Medical Center
John E. Linley: AstraZeneca
Blair H. Smith: University of Dundee
Susan M. Lea: National Cancer Institute
Joanne L. Parker: University of Oxford
Valeriya Lyssenko: Lund University
Simon Newstead: University of Oxford
David L. Bennett: The University of Oxford

Nature, 2025, vol. 646, issue 8084, 404-412

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09326-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:646:y:2025:i:8084:d:10.1038_s41586-025-09326-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09326-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().