Unconventional secretory processing diversifies neuronal ion channel properties

Abstract

N-glycosylation – the sequential addition of complex sugars to adhesion proteins, neurotransmitter receptors, ion channels and secreted trophic factors as they progress through the endoplasmic reticulum and the Golgi apparatus – is one of the most frequent protein modifications. In mammals, most organ-specific N-glycosylation events occur in the brain. Yet, little is known about the nature, function and regulation of N-glycosylation in neurons. Using imaging, quantitative immunoblotting and mass spectrometry, we show that hundreds of neuronal surface membrane proteins are core-glycosylated, resulting in the neuronal membrane displaying surprisingly high levels of glycosylation profiles that are classically associated with immature intracellular proteins. We report that while N-glycosylation is generally required for dendritic development and glutamate receptor surface expression, core-glycosylated proteins are sufficient to sustain these processes, and are thus functional. This atypical glycosylation of surface neuronal proteins can be attributed to a bypass or a hypo-function of the Golgi apparatus. Core-glycosylation is regulated by synaptic activity, modulates synaptic signaling and accelerates the turnover of GluA2-containing glutamate receptors, revealing a novel mechanism that controls the composition and sensing properties of the neuronal membrane.DOI: http://dx.doi.org/10.7554/eLife.20609.001

Assembly, Secretory Pathway Trafficking, and Surface Delivery of Kainate Receptors Is Regulated by Neuronal Activity

“…We note, however, that it has recently been reported that KARs with an immature glycosylation state accumulate at the cell surface, suggesting that not all KARs are processed within the Golgi (Hanus et al., 2016). Like long-term regulation of iGluR synthesis by transcription and translation and short-term regulation by endocytosis and recycling of surface-expressed iGluRs, the intermediate-term processes of trafficking through the secretory pathway are also under tight activity-dependent control.…”

N‐glycan content modulates kainate receptor functional properties

“…The precise glycan composition of oligosaccharide chains conjugated to iGluRs is not clear, although functional surface receptors carry both high‐mannose and complex glycans (Hanus et al . ; Kaniakova et al . ).…”

Conserved Oligomeric Golgi and Neuronal Vesicular Trafficking

“…Neurons have more immature/core N-glycan structures on the cell surface, suggesting that N-glycosylation does not follow the intricate process that results in the complex sugar structures observed in other cell types (Hanus et al 2016) (Fig. 2).…”

“…2). Hanus et al (2016) speculate that proteins with immature N-glycans bypass the Golgi as Golgi disassembly had no effect on PM distribution of these proteins (Hanus et al 2016). Via an unidentified sorting process, proteins could exit the ER/cis-Golgi, without completely traversing the Golgi, and produce fully functional receptors (Hanus et al 2016; Jeyifous et al 2009).…”

“…Hanus et al (2016) speculate that proteins with immature N-glycans bypass the Golgi as Golgi disassembly had no effect on PM distribution of these proteins (Hanus et al 2016). Via an unidentified sorting process, proteins could exit the ER/cis-Golgi, without completely traversing the Golgi, and produce fully functional receptors (Hanus et al 2016; Jeyifous et al 2009). Although GO and GS contain glycosylation enzymes and polysialylated proteins (Mikhaylova et al 2016), it is not yet known if proteins that avoid traditional Golgi trafficking pathways are modified in GO and GS.…”