AimsIn contrast to G protein-coupled receptors or receptor tyrosine kinases, the mechanism underlying ERK activation through nicotine acetylcholine receptors (nAChRs), members of the ligand-gated ion channel family, remains poorly elucidated. This study aimed to delineate the signaling pathway responsible for ERK activation by the α4β2 nAChR subtype, which is implicated in nicotine addiction and various mental disorders. Materials and methodsLoss-of-function strategies and mutants of arrestin2/PKCβII with distinct functional characteristics were employed to identify the cellular components and processes involved in ERK activation. Key findingsERK activation via α4β2 nAChR was observed within the nucleus and necessitated the nuclear translocation of arrestin2 and PKCβII, which exhibited mutual augmentation. Activation of PKCβII by α4β2 nAChR stimulation facilitated the nuclear translocation of arrestin2 by enhancing its interaction with importin β1. Apart from scaffolding ERK activation in the nucleus, arrestin2, in cooperation with GRK2, facilitated the activation of the Src/Syk/PKCβII signaling cascade, leading to the nuclear entry of PKCβII in a Gβγ-dependent manner. Upon nuclear localization, PKCβII underwent ubiquitination by Mdm2 and interacted with MEK1, resulting in ERK activation. In summary, α4β2 nAChR-mediated ERK activation in the nucleus involves the nuclear translocation of arrestin2 and PKCβII, which is reciprocally facilitated via positive feedback augmentation. SignificanceAs α4β2 nAChRs play a pivotal role in various cellular processes including drug addiction and mental disorders, our findings will offer insights into understanding the pathogenesis of α4β2 nAChR-related disorders and may facilitate the development of targeted therapeutic interventions.
Read full abstract