Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
Cell Rep. 2021 Jun 15;35(11):109248. doi: 10.1016/j.celrep.2021.109248.
Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that is insensitive to extracellular Ca and associated with a reduced contribution of P/Q-type Ca channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation, pull-down assays, and proteomics reveal a specific and direct interaction of PRRT2 with P/Q-type Ca channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca sensitivity of the release machinery at glutamatergic synapses.
富含脯氨酸的跨膜蛋白 2（PRRT2）功能丧失突变可引起与谷氨酸能传递的 Ca 依赖性缺陷相关的阵发性疾病。我们发现，PRRT2 的急性或组成型缺失会导致诱发的兴奋性突触后电流（eEPSC）幅度显著降低，该降低对细胞外 Ca 不敏感，并与 P/Q 型 Ca 通道对 EPSC 幅度的贡献减少有关。这种突触表型与由于通道的膜靶向减少而导致的体细胞 P/Q 型 Ca 电流减少平行，而总表达水平不变。共免疫沉淀、下拉测定和蛋白质组学揭示了 PRRT2 与 P/Q 型 Ca 通道的特异性和直接相互作用。在缺乏 PRRT2 的突触前末端，P/Q 型 Ca 通道减少了它们在活性区的聚集，相应地减少了 P/Q 依赖性突触前 Ca 信号。这些数据突出了 PRRT2 在确保谷氨酸能突触释放机制的生理 Ca 敏感性方面的核心作用。
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