Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity

Khosrow Rezvani, Yanfen Teng, David Shim, Mariella De Biasi

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Ubiquitination regulates the degradation, membrane trafficking, and transcription of proteins. At mammalian synapses, the ubiquitin-proteasome system (UPS) influences synaptic transmission and plasticity. Nicotine also has the ability to affect synaptic function via mechanisms that remain partially unknown. We found that nicotine, at concentrations achieved by smokers, reduced proteasomal activity, produced accumulation of ubiquitinated synaptic proteins, and increased total protein levels. In particular, a 24 h exposure to nicotine decreased proteasome-dependent degradation of the α7 nicotinic acetylcholine receptor (nAChR) subunit, as indicated by the accumulation of ubiquitinated α7. The same nicotine treatment increased the levels of the AMPA glutamate receptor subunit GluR1, the NMDA receptor subunit NR2A, the metabotropic receptor mGluR1α, the plasticity factor Homer-1A, and the scaffolding postsynaptic density protein PSD-95, whereas the levels of another scaffolding protein, Shank, were reduced. These changes were associated with an inhibition of proteasomal chymotrypsin-like activity by nicotine. The nAChR antagonist mecamylamine was only partially able to block the effects of nicotine on the UPS, indicating that nAChR activation does not completely explain nicotine-induced inhibition of proteasomal catalytic activity. A competition binding assay suggested a direct interaction between nicotine and the 20S proteasome. These results suggest that the UPS might participate in nicotine-dependent synaptic plasticity.

Original languageEnglish (US)
Pages (from-to)10508-10519
Number of pages12
JournalJournal of Neuroscience
Volume27
Issue number39
DOIs
StatePublished - Sep 26 2007

Keywords

  • Glutamate receptors
  • Mecamylamine
  • Nicotine
  • Nicotinic acetylcholine receptor
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)

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