RT Journal Article
T1 Selective inhibition of cannabinoid CB1 receptor-evoked signalling by the interacting protein GAP43
A1 Maroto Martínez, Irene Berenice
A1 Moreno, Estefanía
A1 Costas Insúa, Carlos
A1 Merino Gracia, Javier
A1 Diez-Alarcia, Rebeca
A1 Álvaro-Blázquez, Alicia
A1 Canales Mayordomo, María Ángeles
A1 Canela, Enric I.
A1 Casadó, Vicent
A1 Urigüen, Leyre
A1 Rodríguez Crespo, José Ignacio
A1 Guzmán Pastor, Manuel
AB Cannabinoids exert pleiotropic effects on the brain by engaging the cannabinoid CB1 receptor (CB1R), a presynaptic metabotropic receptor that regulates key neuronal functions in a highly context-dependent manner. We have previously shown that CB1R interacts with growth-associated protein of 43 kDa (GAP43) and that this interaction inhibits CB1R function on hippocampal excitatory synaptic transmission, thereby impairing the therapeutic effect of cannabinoids on epileptic seizures in vivo. However, the underlying molecular features of this interaction remain unexplored. Here, we conducted mechanistic experiments on HEK293T cells co-expressing CB1R and GAP43 and show that GAP43 modulates CB1R signalling in a strikingly selective manner. Specifically, GAP43 did not affect the archetypical agonist-evoked (i) CB1R/Gi/o protein-coupled signalling pathways, such as cAMP/PKA and ERK, or (ii) CB1R internalization and intracellular trafficking. In contrast, GAP43 blocked an alternative agonist-evoked CB1R-mediated activation of the cytoskeleton-associated ROCK signalling pathway, which relied on the GAP43-mediated impairment of CB1R/Gq/11 protein coupling. GAP43 also abrogated CB1R-mediated ROCK activation in mouse hippocampal neurons, and this process led in turn to a blockade of cannabinoid-evoked neurite collapse. An NMR-based characterization of the CB1R-GAP43 interaction supported that GAP43 binds directly and specifically through multiple amino acid stretches to the C-terminal domain of the receptor. Taken together, our findings unveil a CB1R-Gq/11-ROCK signalling axis that is selectively impaired by GAP43 and may ultimately control neurite outgrowth.
PB Elsevier
SN 0028-3908
YR 2023
FD 2023-12
LK https://hdl.handle.net/20.500.14352/105708
UL https://hdl.handle.net/20.500.14352/105708
LA eng
NO Irene B. Maroto, Estefanía Moreno, Carlos Costas-Insua, Javier Merino-Gracia, Rebeca Diez-Alarcia, Alicia Álvaro-Blázquez, Ángeles Canales, Enric I. Canela, Vicent Casadó, Leyre Urigüen, Ignacio Rodríguez-Crespo, Manuel Guzmán, Selective inhibition of cannabinoid CB1 receptor-evoked signalling by the interacting protein GAP43, Neuropharmacology, Volume 240, 2023, 109712, ISSN 0028-3908, https://doi.org/10.1016/j.neuropharm.2023.109712.
DS Docta Complutense
RD 29 jun 2025