Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity.
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 alpha7 nicotinic acetylcholine receptor (nAChR) subunit, as indicated by the accumulation of ubiquitinated alpha7. The same nicotine treatment increased the levels of the AMPA glutamate receptor subunit GluR1, the NMDA receptor subunit NR2A, the metabotropic receptor mGluR1alpha, 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.
Rezvani
Khosrow
K
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Teng
Yanfen
Y
Shim
David
D
De Biasi
Mariella
M
D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D023421:Models, Animal; D018377:Neurotransmitter Agents / Q000096:biosynthesis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects*; D017470:Receptors, Glutamate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D025801:Ubiquitin / Q000378:metabolism
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D061988:Proteasome Inhibitors; D017470:Receptors, Glutamate; D011978:Receptors, Nicotinic; D025801:Ubiquitin; D009538:Nicotine; D051528:Guanylate Kinases; D046988:Proteasome Endopeptidase Complex