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

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 ?6?2?3 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 ?4?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 Förster resonance energy transfer between ?6?2?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.

SUBMITTER: Henderson BJ 

PROVIDER: S-EPMC3874574 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature