Lützenkirchen Felix P, Zhu Yipeng, Maric Hans M, Boeck Dominik S, Gromova Kira V, Kneussel Matthias
Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
Commun Biol. 2024 Dec 12;7(1):1635. doi: 10.1038/s42003-024-07294-z.
GABAergic synapses critically modulate neuronal excitability, and plastic changes in inhibitory synaptic strength require reversible interactions between GABA receptors (GABARs) and their postsynaptic anchor gephyrin. Inhibitory long-term potentiation (LTP) depends on the postsynaptic recruitment of gephyrin and GABARs, whereas the neurotransmitter GABA can induce synaptic removal of GABARs. 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 GABAR 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 GABARs. 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.
γ-氨基丁酸能（GABAergic）突触对神经元兴奋性起着关键的调节作用，抑制性突触强度的可塑性变化需要GABA受体（GABARs）与其突触后锚定蛋白gephyrin之间的可逆相互作用。抑制性长时程增强（LTP）依赖于gephyrin和GABARs在突触后的募集，而神经递质GABA可诱导GABARs从突触上移除。然而，突触强度可塑性适应的机制和相关因子仍未完全明确。在此，我们表明神经beachin蛋白（Nbea），一种受体转运蛋白，是抑制性突触的组成部分，它与gephyrin相互作用并调节抑制性突触传递的下调。我们发现Nbea向GABA能突触的募集依赖于活性，并且Nbea以蛋白激酶A（PKA）依赖的方式调节GABARs的内化。在缺乏一个Nbea等位基因的杂合神经元中，Nbea的重新表达而非PKA结合缺陷型Nbea突变体的表达挽救了GABARs的内化。我们的数据表明了一种机制，即Nbea介导PKA锚定在抑制性突触后位点以下调GABA能传递。这些数据强调了激酶定位在突触强度调节中的重要性。
