The Ubiquitin Ligase RPM-1 and the p38 MAPK PMK-3 Regulate AMPA Receptor Trafficking

Abstract

Ubiquitination occurs at synapses, yet its role remains unclear. Previous studies demonstrated that the RPM-1 ubiquitin ligase organizes presynaptic boutons at neuromuscular junctions in C. elegans motorneurons. Here we find that RPM-1 has a novel postsynaptic role in interneurons, where it regulates the trafficking of the AMPA-type glutamate receptor GLR-1 from synapses into endosomes. Mutations in rpm-1 cause the aberrant accumulation of GLR-1 in neurites. Moreover, rpm-1 mutations enhance the endosomal accumulation of GLR-1 observed in mutants for lin-10, a Mint2 ortholog that promotes GLR-1 recycling from Syntaxin-13 containing endosomes. As in motorneurons, RPM-1 negatively regulates the pmk-3/p38 MAPK pathway in interneurons by repressing the protein levels of the MAPKKK DLK-1. This regulation of PMK-3 signaling is critical for RPM-1 function with respect to GLR-1 trafficking, as pmk-3 mutations suppress both lin-10 and rpm-1 mutations. Positive or negative changes in endocytosis mimic the effects of rpm-1 or pmk-3 mutations, respectively, on GLR-1 trafficking. Specifically, RAB-5(GDP), an inactive mutant of RAB-5 that reduces endocytosis, mimics the effect of pmk-3 mutations when introduced into wild-type animals, and occludes the effect of pmk-3 mutations when introduced into pmk-3 mutants. By contrast, RAB-5(GTP), which increases endocytosis, suppresses the effect of pmk-3 mutations, mimics the effect of rpm-1 mutations, and occludes the effect of rpm-1 mutations. Our findings indicate a novel specialized role for RPM-1 and PMK-3/p38 MAPK in regulating the endosomal trafficking of AMPARs at central synapses.

The Ubiquitin Ligase MYCBP2 Regulates Transient Receptor Potential Vanilloid Receptor 1 (TRPV1) Internalization through Inhibition of p38 MAPK Signaling

“…We found that MYCBP2-deficiency causes constitutive p38 MAPK activation which, surprisingly, prevented activity-induced internalization of the transient receptor potential vanilloid receptor 1 (TRPV1). This finding contrasts the role of MYCBP2 and p38 MAPK in AMPA receptor internalization in C. elegans (14) as well as the previously described role of p38 MAPK in promoting receptor internalization in mammalians (18 -20). Thus, our findings suggest that p38 MAPK fulfills receptor-dependent versatile roles in the regulation of receptor internalization.…”

“…However, p38 MAPK activation has been demonstrated to promote internalization of -opioid-and AMPA receptors which would be in contrast to our findings (14,18,20,34). Therefore, we tested in the next step whether or not p38 MAPK-activation prevents TRPV1 internalization in MYCBP2-deficient neurons.…”

“…In C. elegans and drosophila loss-of-function mutations in the MYCBP2 orthologs decreased the number of synaptic vesicles at cholinergic and GABAergic synapses in a p38 MAPK-dependent manner (9) and reduced strength of synaptic transmission at neuromuscular junctions (5,12,13). More recently, it was shown that the MYCBP2 ortholog in C. elegans, RPM-1, prevents in central neurons activity-dependent internalization of AMPA receptors by inhibiting p38 MAPK signaling through ubiquitylation of MAPK kinase kinase 12 (MAPKKK12), (14). Loss of RPM-1 caused constitutive activation of p38MAPK leading to an increased internalization of the AMPA receptor ortholog GLR1.…”

The ubiquitin-proteasome pathway and synaptic plasticity

“…Park et al (2009) found that RPM-1 regulates AMPA receptor trafficking in interneurons in C. elegans. RPM-1 works by negatively regulating the levels of DLK-1 (MAPKKK) (Park et al 2009). …”

The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy

“…RPM-1 negatively regulates the MAP kinase pathway of MAPKKK DLK-1, MAPKK MKK-4 and p38 MAPK PMK-3. Recently, this pathway was shown to also regulate trafficking of the AMPA-type glutamate receptor GLR-1 (Park et al, 2009). Destabilization of enhancer binding protein CEBP-1 mRNA has also recently been shown to alter local translation of MAPKKK components in distal axons to disrupt axon morphology and synapse formation in C. elegans (Yan et al, 2009).…”