RT Journal Article
T1 CB1 receptors down-regulate a cAMP/Epac2/PLC pathway to silence the nerve terminals of cerebellar granule cells
A1 Alonso, Beatris
A1 Bartolomé-Martín, David
A1 Ferrero, José Javier
A1 Ramírez-Franco, Jorge
A1 Torres Molina, Magdalena Isabel
A1 Sánchez-Prieto Borja, José
AB Cannabinoid receptors mediate short-term retrograde inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at excitatory synapses. The responses of individual nerve terminals in VGLUT1-pHluorin transfected cerebellar granule cells to cannabinoids have shown that prolonged activation of cannabinoid type 1 receptors (CB1Rs) silences a subpopulation of previously active synaptic boutons. Adopting a combined pharmacological and genetic approach to study the molecular mechanisms of CB1R-induced silencing, we found that adenylyl cyclase inhibition decreases cAMP levels while it increases the number of silent synaptic boutons and occludes the induction of further silencing by the cannabinoid agonist HU-210. Guanine nucleotide exchange proteins directly activated by cAMP (Epac proteins) mediate some of the presynaptic effects of cAMP in the potentiation of synaptic transmission. ESI05, a selective Epac2 inhibitor, and U-73122, the specific inhibitor of phospholipase C (PLC), both augment the number of silent synaptic boutons. Moreover, they abolish the capacity of the Epac activator, 8-(4-chlorophenylthio)-2'-O-methyladenosine 3',5'-cyclic monophosphate monosodium hydrate, to prevent HU-210-induced silencing consistent with PLC signaling lying downstream of Epac2 proteins. Furthermore, Rab3-interacting molecule (RIM)1α KO cells have many more basally silent synaptic boutons (12.9 ± 3.5%) than wild-type cells (1.1 ± 0.5%). HU-210 induced further silencing in these mutant cells, although 8-(4-chlorophenylthio)-2'-O-methyladenosine 3',5'-cyclic monophosphate monosodium hydrate only awoke the HU-210-induced silence and not the basally silent synaptic boutons. This behavior can be rescued by expressing RIM1α in RIM1α KO cells, these cells behaving very much like wild-type cells. These findings support the hypothesis that a cAMP/Epac/PLC signaling pathway targeting the release machinery appears to mediate cannabinoid-induced presynaptic silencing.
PB Wiley
SN 0022-3042
YR 2017
FD 2017
LK https://hdl.handle.net/20.500.14352/129959
UL https://hdl.handle.net/20.500.14352/129959
LA eng
NO Alonso, B., Bartolomé-Martín, D., Ferrero, J.J., Ramírez-Franco, J., Torres, M. and Sánchez-Prieto, J. (2017), CB1 receptors down-regulate a cAMP/Epac2/PLC pathway to silence the nerve terminals of cerebellar granule cells. J. Neurochem., 142: 350-364. https://doi-org.bucm.idm.oclc.org/10.1111/jnc.14059
NO Becas/Contratos:BFU 2013-43163R (José Sánchez Prieto)
NO Ministerio de Economía y Comercio (España)
NO Instituto de Salud Carlos III
NO Comunidad de Madrid
NO Ministerio de Educación, Cultura y Deporte (Madrid)
DS Docta Complutense
RD 13 ene 2026