Journal article

A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes

Quynh N Mai, Priyank Shenoy, Tim Quach, Jeffri S Retamal, Arisbel B Gondin, Holly R Yeatman, Luigi Aurelio, Joshua W Conner, Daniel P Poole, Meritxell Canals, Cameron J Nowell, Bim Graham, Thomas P Davis, Stephen J Briddon, Stephen J Hill, Christopher JH Porter, Nigel W Bunnett, Michelle L Halls, Nicholas A Veldhuis



G-protein-coupled receptors (GPCRs) are traditionally known for signaling at the plasma membrane, but they can also signal from endosomes after internalization to control important pathophysiological processes. In spinal neurons, sustained endosomal signaling of the neurokinin 1 receptor (NK1R) mediates nociception, as demonstrated in models of acute and neuropathic pain. An NK1R antagonist, Spantide I (Span), conjugated to cholestanol (Span-Chol), accumulates in endosomes, inhibits endosomal NK1R signaling, and causes prolonged antinociception. However, the extent to which the Chol-anchor influences long-term location and activity is poorly understood. Herein, we used fluorescent correlatio..

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University of Melbourne Researchers


Awarded by National Institutes of Health

Awarded by Department of Defence

Awarded by National Health and Medical Research Council

Awarded by ARC Centre of Excellence in Convergent BioNano Science and Technology

Awarded by Medical Research Council

Awarded by NHMRC

Funding Acknowledgements

This work was supported by grants from the National Institutes of Health (NS102722, DE026806, DE029951, DK118971 to N. W. B), Department of Defence (W81XWH1810431 to N. W. B.), National Health and Medical Research Council (63303 to N. W. B., 1049682 to N. W. B. and B. G., 1031886 to N. W. B. and D. P. P, 1083054 to N. W. B., M. L. H., M. C., C. J. P., and T. P. D.), ARC Centre of Excellence in Convergent BioNano Science and Technology (CE14100036 to N. W. B., T. P. D., C. J. P., N. A. V.), and Medical Research Council (MR/N020081/1 to S. J. B., S. J. H.). M. L. H. was an NHMRC RD Wright Fellow (1061687). Q. N. M. was part of the Joint Award Doctoral Training Centre in Molecular Pharmacology and Drug Discovery at Monash University (Australia) and the University of Nottingham (UK).