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Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
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Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
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Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
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Journal Article
Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
2023
Overview
The type-1 cannabinoid receptor (CB
1
R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB
1
R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the
C
-terminal, intracellular domain of CB
1
R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB
1
R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB
1
R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB
1
R that hampers CB
1
R-mediated effects on hippocampal circuit function.
Cannabis impacts our brain by engaging the CB
1
receptor. Here, the authors identify a protein called GAP43 that interacts with CB
1
and blocks its synaptic functions. This finding provides a conceptual view to understand how CB
1
acts in the brain.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/44
/ 13/95
/ 14/19
/ 14/5
/ 38/35
/ 64/110
/ 64/60
/ 82/16
/ 82/29
/ 82/51
/ 82/58
/ 82/80
/ 82/83
/ 9/26
/ 9/30
/ 9/74
/ Animals
/ Brain
/ Cannabis
/ Circuits
/ Humanities and Social Sciences
/ Mice
/ Proteins
/ Receptor, Cannabinoid, CB1 - genetics
/ Receptor, Cannabinoid, CB1 - metabolism
/ Receptors, Cannabinoid - metabolism
/ Science
/ Synapses
