One of the hallmarks of Parkinson’s disease (PD) is the alteration in the expression and function of NMDA receptor (NMDAR) and cannabinoid receptor 1 (CBsub.1R). The presence of CBsub.1R-NMDAR ...complexes has been described in neuronal primary cultures. The activation of CBsub.1R in CBsub.1R-NMDAR complexes was suggested to counteract the detrimental NMDAR overactivation in an AD mice model. Thus, we aimed to explore the role of this receptor complex in PD. By using Bioluminescence Resonance Energy Transfer (BRET) assay, it was demonstrated that α-synuclein induces a reorganization of the CBsub.1R-NMDAR complex in transfected HEK-293T cells. Moreover, α-synuclein treatment induced a decrease in the cAMP and MAP kinase (MAPK) signaling of both CBsub.1R and NMDAR not only in transfected cells but also in neuronal primary cultures. Finally, the interaction between CBsub.1R and NMDAR was studied by Proximity Ligation Assay (PLA) in neuronal primary cultures, where it was observed that the expression of CBsub.1R-NMDAR complexes was decreased upon α-synuclein treatment. These results point to a role of CBsub.1R-NMDAR complexes as a new therapeutic target in Parkinson’s disease.
Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. ...Noradrenergic fibers from locus coeruleus project to the DCN, and alpha2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na.sup.+ leak channel NALCN in mice and found that its presence was required for spontaneous firing in cartwheel cells. Activation of alpha2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, alpha2-dependent enhancement of synaptic strength was also absent in the knockout. GABA.sub.B receptors mediated inhibition through NALCN as well, acting on the same population of channels as alpha2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.
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