Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor

Xiaona Li, Nathan D. Winters, Shubhi Pandey, Colten Lankford, Hannah M. Stoveken, Emery Smith, Chu-Ting Chang, Stefano Zucca, Louis Scampavia, Timothy Spicer and Kirill A. Martemyanov ()
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Xiaona Li: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Nathan D. Winters: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Shubhi Pandey: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Colten Lankford: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Hannah M. Stoveken: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Emery Smith: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Chu-Ting Chang: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Stefano Zucca: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Louis Scampavia: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Timothy Spicer: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Kirill A. Martemyanov: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The endogenous opioid system provides powerful control over emotions, nociception, and motivation among many other fundamental nervous system functions. Its major components include a panel of opioid peptides that activate four canonical inhibitory opioid receptors. However, its regulatory principles are not fully understood including the existence of additional receptors and other elements. In this study we report the identification of a receptor for the opioid peptide dynorphin. By conducting a screen of a custom library of neuropeptides, we found that orphan receptor GPR139 binds to and is activated by a series of dynorphin peptides. Unlike other opioid receptors, GPR139 couples to Gq/11 and avoids β-arrestin, providing excitatory signaling that homeostatically scales the inhibitory response of neurons to dynorphin. This introduces a non-canonical dynorphin receptor as an essential component of the opioid system.

Date: 2025
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DOI: 10.1038/s41467-025-62133-x

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