RT Journal Article
T1 CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling
A1 Palazuelos Diego, Javier
A1 Ortega, Zaira
A1 Díaz-Alonso, Javier
A1 Guzmán Pastor, Manuel
A1 Galve Roperh, Ismael
AB The endocannabinoid system is knownto regulate neural progenitor (NP) cell proliferation and neurogenesis. In particular, CB2 cannabinoid receptors have been shown to promote NP proliferation. As CB2 receptors are not expressed in differentiated neurons, CB2-selective agonists are promising candidates to manipulate NP proliferation and indirectly neurogenesis by overcoming the undesired psychoactive effects of neuronal CB1 cannabinoid receptor activation. Here, by using NP cells, brain organotypic cultures, and in vivo animal models, we investigated the signal transduction mechanism involved in CB2 receptorinduced NP cell proliferation and neurogenesis. Exposure of hippocampal HiB5 NP cells to the CB2 receptor-selective agonist HU-308 led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, which, by inhibiting its downstream target p27Kip1, induced NP proliferation. Experiments conducted with the CB2 receptor-selective antagonist SR144528, inhibitors of the PI3K/Akt/mTORC1 axis, and CB2 receptor transienttransfection vector further supported that CB2 receptors control NP cell proliferation via activation of mTORC1 signaling. Likewise, CB2 receptor engagement induced cell proliferation in an mTORC1-dependent manner both in embryonic cortical slices and in adult hippocampal NPs. Thus, HU-308 increased ribosomal protein S6 phosphorylation and 5-bromo-2*-deoxyuridine incorporation in wild-type but not CB2 receptor-deficient NPs of the mouse subgranular zone. Moreover, adult hippocampal NP proliferation induced by HU-308 and excitotoxicity was blocked by the mTORC1 inhibitor rapamycin. Altogether, these findings provide a mechanism of action and a rationale for the use of nonpsychotomimetic CB2 receptor-selective ligands as a novel strategy for the control of NP cell proliferation and neurogenesis.
PB Elsevier
SN 0021-9258
YR 2012
FD 2012
LK https://hdl.handle.net/20.500.14352/89005
UL https://hdl.handle.net/20.500.14352/89005
LA eng
NO Palazuelos, Javier, et al. «CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling». Journal of Biological Chemistry, vol. 287, n.o 2, enero de 2012, pp. 1198-209. https://doi.org/10.1074/jbc.M111.291294.
NO Ministerio de Ciencia e Innovación (España)
NO Comunidad de Madrid
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 7 abr 2025