Neurobeachin regulates receptor downscaling at GABAergic inhibitory synapses in a protein kinase A-dependent manner.

Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE

Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]-

Cyclic AMP-Dependent Protein Kinases*/metabolism ; Receptors, GABA-A*/metabolism ; Receptors, GABA-A*/genetics ; Synapses*/metabolism ; GABAergic Neurons*/metabolism ; GABAergic Neurons*/physiology; Animals ; Mice ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Carrier Proteins/metabolism ; Carrier Proteins/genetics ; Synaptic Transmission ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Humans

GABAergic synapses critically modulate neuronal excitability, and plastic changes in inhibitory synaptic strength require reversible interactions between GABA A receptors (GABA A Rs) and their postsynaptic anchor gephyrin. Inhibitory long-term potentiation (LTP) depends on the postsynaptic recruitment of gephyrin and GABA A Rs, whereas the neurotransmitter GABA can induce synaptic removal of GABA A Rs. However, the mechanisms and players underlying plastic adaptation of synaptic strength are incompletely understood. Here we show that neurobeachin (Nbea), a receptor trafficking protein, is a component of inhibitory synapses, interacts with gephyrin and regulates the downscaling of inhibitory synaptic transmission. We found that the recruitment of Nbea to GABAergic synapses is activity-dependent and that Nbea regulates GABA A R internalization in a protein kinase A (PKA)-dependent manner. In heterozygous neurons lacking one Nbea allele, re-expression of Nbea but not expression of a PKA binding-deficient Nbea mutant rescued the internalization of GABA A Rs. Our data suggest a mechanism by which Nbea mediates PKA anchoring at inhibitory postsynaptic sites to downregulate GABAergic transmission. They emphasize the importance of kinase positioning in the regulation of synaptic strength.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)

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KN556/16-1 Deutsche Forschungsgemeinschaft (German Research Foundation); KN556/17-1 Deutsche Forschungsgemeinschaft (German Research Foundation)

EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
0 (gephyrin)
0 (Receptors, GABA-A)
0 (Membrane Proteins)
0 (Carrier Proteins)
0 (Nerve Tissue Proteins)

Date Created: 20241212 Date Completed: 20241212 Latest Revision: 20241215

20250114

PMC11638247

10.1038/s42003-024-07294-z

39668217