α7 nicotinic acetylcholine receptor upregulation by anti-apoptotic Bcl-2 proteins

Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of alpha 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 alpha 7 nAChRs. Leveraging the robust recombinant expression of alpha 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 alpha 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 alpha 7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal alpha 7 receptor assembly. These results demonstrate that Bcl-2 proteins link alpha 7 nAChR assembly to cell survival pathways.