Neuroscience Graduate Program, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2024 Oct 22;43(10):114841. doi: 10.1016/j.celrep.2024.114841. Epub 2024 Oct 10.
The WW and C2 domain-containing protein (WWC2) is implicated in several neurological disorders. Here, we demonstrate that WWC2 interacts with inhibitory, but not excitatory, postsynaptic scaffolds, consistent with prior proteomic identification of WWC2 as a putative component of the inhibitory postsynaptic density. Using mice lacking WWC2 expression in excitatory forebrain neurons, we show that WWC2 suppresses γ-aminobutyric acid type-A receptor (GABAR) incorporation into the plasma membrane and regulates HAP1 and GRIP1, which form a complex promoting GABAR recycling to the membrane. Inhibitory synaptic transmission is increased in CA1 pyramidal cells lacking WWC2. Furthermore, unlike the WWC2 homolog KIBRA (kidney/brain protein; WWC1), a key regulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking at excitatory synapses, the deletion of WWC2 does not affect synaptic AMPAR expression. In contrast, loss of KIBRA does not affect GABAR membrane expression. These data reveal synapse class-selective functions for WWC proteins as regulators of ionotropic neurotransmitter receptors and provide insight into mechanisms regulating GABAR membrane expression.
WW 和 C2 结构域蛋白（WWC2）与几种神经紊乱有关。在这里，我们证明 WWC2 与抑制性而不是兴奋性突触后支架相互作用，这与之前的蛋白质组学鉴定一致，即 WWC2 是抑制性突触后密度的一个假定成分。使用在兴奋性前脑神经元中缺乏 WWC2 表达的小鼠，我们表明 WWC2 抑制γ-氨基丁酸 A 型受体（GABAR）整合到质膜中，并调节 HAP1 和 GRIP1，它们形成一个促进 GABAR 向膜再循环的复合物。在缺乏 WWC2 的 CA1 锥体神经元中，抑制性突触传递增加。此外，与兴奋性突触中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）运输的关键调节因子 WWC2 同系物 KIBRA（肾脏/大脑蛋白；WWC1）不同，WWC2 的缺失不影响突触 AMPAR 的表达。相比之下，KIBRA 的缺失不影响 GABAR 膜表达。这些数据揭示了 WWC 蛋白作为离子型神经递质受体调节剂的突触类选择性功能，并为调节 GABAR 膜表达的机制提供了深入了解。
