Nat Commun | Luo Fujun's team reveals that neurexins regulates the aggregation and function of G-protein coupled GABAB receptors in the presynaptic active area

Neurexins are evolutionarily conserved cell adhesion molecules that play a key role in synapse formation and neural circuit function.

Its gene mutations have also been reported to be closely associated with various neuropsychiatric diseases such as autism spectrum disorders.

In vertebrates, neurexins are encoded by three different genes (Nrxn1, Nrxn2, and Nrxn3); each gene expresses long α- and short β-neurexin driven by independent promoters.

In addition, the splicing of neurexins at different sites has led to the generation of thousands of splice variants.

Different subtypes of Neurexins and their splice variants may exhibit specific expression patterns in different neurons, and interact with different types of ligands to play important and different roles in specific neuronal circuits.
The function of regulation.

On April 22, 2021, the Luo Fujun team and the Stanford University Thomas Südhof team once again collaborated to publish an article Neurexins regulate presynaptic GABAB-receptors at central synapses in Nature Communications, revealing the positioning and function of Neurexins in regulating presynaptic GABAB receptors Plays an important role.

This is the two teams following the article Neurexins cluster Ca2+ channels within the presynaptic active zone [1] published in the EMBO J magazine in March 2020, which further proves that Neurexins, as a key organizer, plays a fine role in the molecular structure of the presynaptic active zone.
。 The adjustment.In order to achieve the regulation of the rapid and precise release of neurotransmitters, the presynaptic active area performs four key functions in the nerve endings with a nano- and micro-level precision organization: binding synaptic vesicles at the release site, and maturing synaptic vesicles.
Prepare rapid Ca2+ trigger fusion, gather voltage-gated Ca2+ channels, and coordinate the precise docking of postsynaptic nanopillars.

Studies have shown that the important functions of the presynaptic active region are mediated by evolutionarily conserved key molecules, including RIM, RIM binding protein, ELKS/Bruchpilot and Munc13.

These molecules interact with other signaling proteins to regulate the number of Ca2+ channels and their tight coupling with synaptic vesicles.

In addition, the expression, distribution and functional characteristics of Ca2+ channels in the presynaptic active area may also be extensively regulated by various G protein-coupled receptors, and induce various forms of short-term and long-term synaptic plasticity, thereby Greatly enhance the ability of synaptic computing.

GABAB receptors are G protein-coupled receptors that are specifically activated by GABA, the most important inhibitory neurotransmitter in the mammalian brain.

GABAB receptors are widely expressed in the pre-synaptic and post-synaptic of almost all neurons and in astrocytes, and play an important role in regulating synaptic function and short-term plasticity.

The activation of presynaptic GABAB receptors significantly inhibits the release of neurotransmitters in excitatory and inhibitory synapses by inhibiting the activity of Ca2+ channels or other mechanisms that are independent of Ca2+ channels.

However, the molecular mechanism of GABAB signal transduction complex assembly is still unclear.

Researchers combine molecular, genetic, viral, optogenetics, electrophysiology, immunohistochemistry, super-resolution optical microscopy imaging technology and other interdisciplinary methods to systematically compare four different model synapses in the center, including the calyx of the brainstem.
Held excitatory synapses, the excitability and inhibitory synapses of hippocampal CA1 pyramidal neurons, and the inhibitory synapses of cerebellar blue cells.
It was found that knocking out all neurexins can effectively reduce the effect of G-protein coupled GABAB receptors on nerves.
Regulation of transmitter release.

STORM super-resolution optical imaging further reveals that the loss of neurexins leads to impaired spatial distribution of GABAB receptors at synaptic terminals.

This result suggests for the first time that neurexins is a key molecule that regulates presynaptic G-protein coupled metabotropic receptors, thereby expanding the role of neurexins as a central organizer in the presynaptic active area.

Researcher Luo Fujun from the Biological Island Laboratory is the independent corresponding author of the paper, and Dr.
Alessander Sclip from the Thomas Südhof team of Stanford University at Stanford University made an equally important contribution.

Original link:Bio-Island Laboratory Luo Fujun's research group recruits post-doctorate post.
This research group focuses on the synaptic and molecular mechanisms of neural circuits, using genetically modified small Mouse and molecular and genetic methods, combined with interdisciplinary techniques such as patch clamp recording, optical imaging, immunohistochemistry, and behavior, systematically analyze how neuronal circuits specifically establish and regulate synaptic connections, thereby mediating animal behavior.

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Luo F, Sclip A, Jiang M, Südhof TC.
(2020).
Neurexins cluster Ca2+ channels within the presynaptic active zone.
EMBO J.
39(7): e103208.
doi: 10.
15252/embj.
2019103208.
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