PORCN Negatively Regulates AMPAR Function Independently of Subunit Composition and the Amino-Terminal and Carboxy-Terminal Domains of AMPARs.

Most fast excitatory synaptic transmissions in the mammalian brain are mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), which are ligand-gated cation channels. The membrane expression level of AMPARs is largely determined by auxiliary subunits in AMPAR macromolecules, including porcupine O-acyltransferase (PORCN), which negatively regulates AMPAR trafficking to the plasma membrane. However, whether PORCN-mediated regulation depends on AMPAR subunit composition or particular regions of a subunit has not been determined. We systematically examined the effects of PORCN on the ligand-gated current and surface expression level of GluA1, GluA2, and GluA3 AMPAR subunits, alone and in combination, as well as the PORCN-GluA interaction in heterologous HEK293T cells. PORCN inhibited glutamate-induced currents and the surface expression of investigated GluA AMPAR subunits in a subunit-independent manner. These inhibitory effects required neither the amino-terminal domain (ATD) nor the carboxy-terminal domain (CTD) of GluA subunits. In addition, PORCN interacted with AMPARs independently of their ATD or CTD. Thus, the functional inhibition of AMPARs by PORCN in transfected heterologous cells was independent of the ATD, CTD, and subunit composition of AMPARs.