The inhibitory glycine receptor (GlyR) in developing spinal neurones is internalized efficiently upon antagonist inhibition. Here we used surface labeling combined with affinity purification to show that homopentameric ␣1 GlyRs generated in Xenopus oocytes are proteolytically nicked into fragments of 35 and 13 kDa upon prolonged incubation. Nicked GlyRs do not exist at the cell surface, indicating that proteolysis occurs exclusively in the endocytotic pathway. Consistent with this interpretation, elevation of the lysosomal pH, but not the proteasome inhibitor lactacystin, prevents GlyR cleavage. Prior to internalization, ␣1 GlyRs are conjugated extensively with ubiquitin in the plasma membrane. Our results are consistent with ubiquitination regulating the endocytosis and subsequent proteolysis of GlyRs residing in the plasma membrane. Ubiquitin-conjugating enzymes thus may have a crucial role in synaptic plasticity by determining postsynaptic receptor numbers.The efficiency of synaptic transmission depends critically on a dense packing of neurotransmitter receptors in the postsynaptic membrane. At fast synapses, ligand-gated ion channels (LGICs) 1 mediate the postsynaptic response. Different lines of evidence indicate that the distribution and density of LGICs in the plasma membrane are regulated tightly. In differentiating muscle fibers, the formation of a densely packed postsynaptic matrix of nicotinic acetylcholine receptors (nAChRs) at the developing motor endplate requires restriction of gene expression to subsynaptic nuclei, efficient internalization and degradation of extrasynaptic receptors, synaptic clustering by rapsyn, and slowing of the turnover of synaptically accumulated nAChRs (1, 2). Inversely, muscle denervation (2) or blockade of neurotransmission by ␣-bungarotoxin (3) causes a loss of nAChRs from the postsynaptic membrane because of an increased rate of protein turnover (4). Because nAChR degradation occurs only after internalization and lysosomal targeting of the receptor protein (4, 5
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.