Exclusive or promiscuous? Role(s) of the moonlighting auxiliary subunit PORCN in AMPA receptor physiology

AMPA型谷氨酸受体（AMPA-type glutamate receptor，AMPAR）是哺乳动物中枢神经系统中主要的兴奋性神经递质受体。AMPAR复合物组装为四个离子通道孔形成亚基GluA 1 -4和多种调节受体运输和门控的辅助亚基的异源四聚体。除了充分研究的跨膜AMPA受体调节蛋白（TARP）和cornichons（CNIH-2/3），最近的质谱分析显示了令人惊讶的大量额外的AMPAR相关蛋白。了解这个庞大而多样的蛋白质集合如何调节AMPAR是一个重要的挑战。新发现的AMPAR相互作用蛋白之一是棕榈酰转移酶豪猪（PORCN）。首次实验证据表明，PORCN可以稳定神经元AMPAR复合物，从而增强突触能传递。PORCN除了在AMPAR信号通路中扮演兼职角色外，还在Wnt信号通路中扮演着重要的角色，本研究拟运用细胞生物学、生物化学和电生理学等多学科的方法，对PORCN在AMPAR信号通路中的作用进行深入研究。此外，我们将解开调节PORCN多功能性的分子机制，从而显着增加我们对兼职蛋白质的理解。

AMPA-type glutamate receptors (AMPARs) are the major excitatory neurotransmitter receptors in the mammalian central nervous system. AMPAR complexes assemble as heterotetramers of the four ion channel pore-forming subunits GluA1-4 and a variety of auxiliary subunits that modulate receptor trafficking and gating. In addition to the well-studied transmembrane AMPA receptor regulatory proteins (TARPs) and cornichons (CNIH-2/3), recent mass spectrometric analyses revealed a surprisingly high number of additional AMPAR-associated proteins. Understanding how this large and diverse protein collection modulates AMPARs is an important challenge.One of the newly discovered AMPAR-interacting proteins is the palmitoyl transferase porcupine (PORCN). First experimental evidence indicates that PORCN can stabilize neuronal AMPAR complexes and thereby enhances glutamatergic synaptic transmission. Besides its moonlighting role in AMPAR signaling, it has been reported that PORCN serves a canonical function in Wnt signaling.Here, we intend to apply a multi-disciplinary approach combining cell-biological, biochemical and electrophysiological techniques in order to investigate the role of PORCN in AMPAR physiology in more detail. In addition, we will unravel the molecular mechanisms that regulate PORCN´s multi-functionality and thereby significantly increase our understanding of moonlighting proteins.