CB1 receptors down -regulate a cAMP/Epac2/PLC pathway to silence the nerve terminals of cerebellar granule cells

被引:14
作者
Alonso, Beatris [1 ,2 ]
Bartolome-Martin, David [1 ,2 ]
Javier Ferrero, Jose [1 ,2 ]
Ramirez-Franco, Jorge [1 ,2 ]
Torres, Magdalena [1 ,2 ]
Sanchez-Prieto, Jose [1 ,2 ]
机构
[1] Univ Complutense, Fac Vet, Dept Bioquim, E-28040 Madrid, Spain
[2] Hosp Clin San Carlos, Inst Invest Sanitaria, Madrid, Spain
关键词
cAMP; CB1; receptors; cerebellar granule cells; Epac2; PLC; presynaptic silencing; RIM1; alpha; BETA-ADRENERGIC-RECEPTORS; LONG-TERM DEPRESSION; GLUTAMATE RELEASE; RIM PROTEINS; NEUROTRANSMITTER RELEASE; ENDOCANNABINOID RELEASE; CANNABINOID RECEPTORS; SYNAPTIC PLASTICITY; PHOSPHOLIPASE-C; CA2+ CHANNELS;
D O I
10.1111/jnc.14059
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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'-0-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)1 alpha 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 RIM1 alpha in RIM 1 alpha 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.
引用
收藏
页码:350 / 364
页数:15
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