Details

Autor(en) / Beteiligte

• Tong, Xia-Jing
• López-Soto, Eduardo Javier
• Li, Lei
• Liu, Haowen
• Nedelcu, Daniel
• Lipscombe, Diane
• Hu, Zhitao
• Kaplan, Joshua M.

Titel

Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels

Ist Teil von

• Neuron (Cambridge, Mass.), 2017-07, Vol.95 (2), p.326-340.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post-synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here, we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/α2δ), decreasing UNC-36 abundance at pre-synaptic elements. Retrograde inhibition is mediated by a soluble form of NRX-1’s ectodomain, which is released from the post-synaptic membrane by the SUP-17/ADAM10 protease. Mammalian Neurexin-1α binds α2δ-3 and decreases CaV2.2 current in transfected cells, whereas Neurexin-1α has no effect on CaV2.2 reconstituted with α2δ-1 and α2δ-2. Collectively, these results suggest that α-Neurexin binding to α2δ is a conserved mechanism for regulating synaptic transmission. •Mouse and C. elegans α-Neurexins bind CaVα2δ with high affinity•C. elegans NRX-1 inhibits ACh release by binding to pre-synaptic UNC-36/α2δ•SUP-17/ADAM10 cleaves NRX-1 and the shed ectodomain inhibits ACh release•Mouse α-Neurexin inhibits the activity of CaV2.2 channels that contain α2δ-3 Retrograde synaptic signals allow post-synaptic cells to dictate changes in the strength and plasticity of their synaptic inputs. Tong et al. show that proteolytic shedding of a post-synaptic adhesion molecule (α-Neurexin) inhibits release by directly binding to pre-synaptic calcium channels.