Abstract
Most fast excitatory synaptic transmissions in the mammalian brain are mediated by α-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.
Highlights
Most fast excitatory synaptic transmissions in the mammalian brain are mediated by α -amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), which are ligand-gated cation channels
We showed that porcupine O-acyltransferase (PORCN) inhibits glutamate-induced currents and amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) surface expression in an AMPAR subunit-independent manner in heterologous cells
To investigate whether the functional inhibition of AMPARs by PORCN depended on AMPAR subunit composition, we measured glutamate-induced currents via the whole-cell patch clamping of HEK293T cells transfected with various AMPAR subunits alone or in combination with stargazin and/or PORCN
Summary
Most fast excitatory synaptic transmissions in the mammalian brain are mediated by α -amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), which are ligand-gated cation channels. Genetic and proteomic studies have revealed more than a dozen auxiliary subunits, including transmembrane AMPAR regulatory proteins [TARPs; (Chen et al, 1999, 2000; Hashimoto et al, 1999; Tomita et al, 2003; Rouach et al, 2005)], cornichon homolog 2/3 [CNIH-2/3; (Schwenk et al, 2009; Kato et al, 2010; Herring et al, 2013)], germ cell-specific gene 1-like protein [GSG1L; (Shanks et al, 2012; McGee et al, 2015; Gu et al, 2016)], abhydrolase domain containing 6 [ABHD6; (Wei et al, 2016, 2017)], and porcupine O-acyltransferase [PORCN; (Erlenhardt et al, 2016)] These auxiliary subunits modulate membrane localization, synaptic targeting, interorganelle trafficking, and the channel kinetics of AMPARs [reviewed in Jackson and Nicoll (2011), Cheng et al (2012), Straub and Tomita (2012), Bettler and Fakler (2017), Bissen et al (2019)]
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