A Novel Effect of PDLIM5 In α7 Nicotinic Acetylcholine Receptors Up-Regulation And Surface Expression

Abstract

α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are expressed widely in the brain, where they contribute to a variety of behaviors including arousal and cognition, participate in a number of neurodegenerative disorders including Alzheimer’s and Parkinson’s disease, and is responsible for nicotine addiction. Although recent studies indicate that the PDZ-containing proteins comprising PSD-95 family co-localize with nicotinic acetylcholine receptors and mediate downstream signaling in the neurons, the mechanisms by which α7nAChRs are regulated are still less well understood. Here we show that the regulation of the α7nAChRs is controlled by PDLIM5 in the endogenous PDZ domain proteins family. We find that chronic exposure to 1 μM nicotine up-regulated both α7, β2-contained nAChRs and PDLIM5 in primary cultured hippocampal neurons, and the up-regulation of α7nAChRs and PDLIM5 is increased more on the cell membrane than the cytoplasm. Interestingly, the α7nAChRs and β2nAChRs display distinct patterns of expression, with α7 co-localized more with PDLIM5. Meanwhile, PDLIM5 interacts with native brain α7 but not β2 nAChRs in neurons. Moreover, knocking down of PDLIM5 in heterologous cells abolishes nicotine-induced up-regulation of α7nAChRs. In cultured hippocampal neurons, shRNA against PDLIM5 decreased both surface clustering of α7nAChRs and α7nAChRs mediated currents. Proteomics analysis shows PDLIM5 interacts with α7nAChRs through the PDZ domain and the interaction between PDLIM5 and α7nAChRs can be promoted by nicotine. Collectively, our data suggest a novel cellular role of PDLIM5 in regulating α7nAChRs, which may be relevant to plastic changes in the nervous system.