Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors.
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abstract
Chronic exposure to nicotine up-regulates high sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain. This up-regulation partially underlies addiction and may also contribute to protection against Parkinson's disease. nAChRs containing the 6 subunit (6* nAChRs) are expressed in neurons in several brain regions, but comparatively little is known about the effect of chronic nicotine on these nAChRs. We report here that nicotine up-regulates 6* nAChRs in several mouse brain regions (substantia nigra pars compacta, ventral tegmental area, medial habenula, and superior colliculus) and in neuroblastoma 2a cells. We present evidence that a coat protein complex I (COPI)-mediated process mediates this up-regulation of 6* or 4* nAChRs but does not participate in basal trafficking. We show that 623 nAChR up-regulation is prevented by mutating a putative COPI-binding motif in the 3 subunit or by inhibiting COPI. Similarly, a COPI-dependent process is required for up-regulation of 42 nAChRs by chronic nicotine but not for basal trafficking. Mutation of the putative COPI-binding motif or inhibition of COPI also results in reduced normalized Frster resonance energy transfer between 623 nAChRs and COP subunits. The discovery that nicotine exploits a COPI-dependent process to chaperone high sensitivity nAChRs is novel and suggests that this may be a common mechanism in the up-regulation of nAChRs in response to chronic nicotine.
Henderson, B. J., Srinivasan, R., Nichols, W. A., Dilworth, C. N., Gutierrez, D. F., Mackey, E., ... Lester, H. A.
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Henderson, Brandon J||Srinivasan, Rahul||Nichols, Weston A||Dilworth, Crystal N||Gutierrez, Diana F||Mackey, Elisha DW||McKinney, Sheri||Drenan, Ryan M||Richards, Christopher I||Lester, Henry A
