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SGIP1 binding to the α-helical H9 domain of cannabinoid receptor 1 promotes axonal surface expression

Fletcher-Jones, Alexandra; Spackman, Ellen; Craig, Tim J.; Nakamura, Yasuko; Wilkinson, Kevin A.; Henley, Jeremy M.

SGIP1 binding to the α-helical H9 domain of cannabinoid receptor 1 promotes axonal surface expression Thumbnail


Authors

Alexandra Fletcher-Jones

Ellen Spackman

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Dr Tim Craig Tim.Craig@uwe.ac.uk
Associate Professor of Neuroscience

Yasuko Nakamura

Kevin A. Wilkinson

Jeremy M. Henley



Abstract

Endocannabinoid signalling mediated by cannabinoid receptor 1 (CB1R, also known as CNR1) is critical for homeostatic neuromodulation of both excitatory and inhibitory synapses. This requires highly polarised axonal surface expression of CB1R, but how this is achieved remains unclear. We previously reported that the α-helical H9 domain in the intracellular C terminus of CB1R contributes to axonal surface expression by an unknown mechanism. Here, we show in rat primary neuronal cultures that the H9 domain binds to the endocytic adaptor protein SGIP1 to promote CB1R expression in the axonal membrane. Overexpression of SGIP1 increases CB1R axonal surface localisation but has no effect on CB1R lacking the H9 domain (CB1RΔH9). Conversely, SGIP1 knockdown reduces axonal surface expression of CB1R but does not affect CB1RΔH9. Furthermore, SGIP1 knockdown diminishes CB1R-mediated inhibition of presynaptic Ca2+ influx in response to neuronal activity. Taken together, these data advance mechanistic understanding of endocannabinoid signalling by demonstrating that SGIP1 interaction with the H9 domain underpins axonal CB1R surface expression to regulate presynaptic responsiveness.

Citation

Fletcher-Jones, A., Spackman, E., Craig, T. J., Nakamura, Y., Wilkinson, K. A., & Henley, J. M. (2024). SGIP1 binding to the α-helical H9 domain of cannabinoid receptor 1 promotes axonal surface expression. Journal of Cell Science, 137(11), Article jcs261551. https://doi.org/10.1242/jcs.261551

Journal Article Type Article
Acceptance Date Apr 30, 2024
Online Publication Date Jun 12, 2024
Publication Date Jun 12, 2024
Deposit Date Jun 21, 2024
Publicly Available Date Jun 21, 2024
Journal Journal of Cell Science
Print ISSN 0021-9533
Electronic ISSN 1477-9137
Publisher Company of Biologists
Peer Reviewed Peer Reviewed
Volume 137
Issue 11
Article Number jcs261551
DOI https://doi.org/10.1242/jcs.261551
Keywords SGIP1, Presynapse, SH3GL interacting endocytic adaptor 1, Cannabinoid receptor 1, Endocytosis, Synaptic transmission, Endocannabinoid system
Public URL https://uwe-repository.worktribe.com/output/12054202

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