Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors

作者：Henderson Brandon J; Srinivasan Rahul; Nichols Weston A; Dilworth Crystal N; Gutierrez Diana F; Mackey Elisha D W; McKinney Sheri; Drenan Ryan M; Richards Christopher I; Lester Henry A^*

来源：Journal of General Physiology, 2014, 143(1): 51-66.

DOI：10.1085/jgp.201311102

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 alpha 6 subunit (alpha 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 alpha 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 alpha 6* or alpha 4* nAChRs but does not participate in basal trafficking. We show that alpha 6 beta 2 beta 3 nAChR up-regulation is prevented by mutating a putative COPI-binding motif in the beta 3 subunit or by inhibiting COPI. Similarly, a COPI-dependent process is required for up-regulation of alpha 4 beta 2 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 Forster resonance energy transfer between alpha 6 beta 2 beta 3 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.

• 出版日期2014-1