?7 nicotinic acetylcholine receptor upregulation by anti-apoptotic Bcl-2 proteins.

ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of ?7-type nAChRs in neuropsychiatric as well as immunological and oncological diseases makes them attractive targets for pharmaceutical development. Recently, we identified NACHO as an essential chaperone for ?7 nAChRs. Leveraging the robust recombinant expression of ?7 nAChRs with NACHO, we utilized genome-wide cDNA library screening and discovered that several anti-apoptotic Bcl-2 family proteins further upregulate receptor assembly and cell surface expression. These effects are mediated by an intracellular motif on ?7 that resembles the BH3 binding domain of pro-apoptotic Bcl-2 proteins, and can be blocked by BH3 mimetic Bcl-2 inhibitors. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous ?7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal ?7 receptor assembly. These results demonstrate that Bcl-2 proteins link ?7 nAChR assembly to cell survival pathways.

SUBMITTER: Dawe GB 

PROVIDER: S-EPMC6588605 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature