A novel effect of PDLIM5 in α7 nicotinic acetylcholine receptor upregulation and surface expression

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 1; p. 64
• Main Authors: Li, Zi-Lin, Gou, Chen-Yu, Wang, Wen-Hui, Li, Yuan, Cui, Yu, Duan, Jing-Jing, Chen, Yuan
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 2022; Springer Nature B.V
• Subjects: Abnormalities; Acetylcholine receptors (nicotinic); Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Addictions; alpha7 Nicotinic Acetylcholine Receptor - biosynthesis; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Behavior, Addictive - physiopathology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Calorimetry; Cell Biology; Cell Line, Tumor; Cell Membrane - metabolism; Cell membranes; Central nervous system; Chronic exposure; Clustering; Cognition; Cytoplasm; HEK293 Cells; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Humans; Life Sciences; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; Nervous system; Neurodegenerative diseases; Neurons; Neurons - metabolism; Nicotine; Nicotine - pharmacology; Original; Original Article; Plasticity; Postsynaptic density proteins; Protein Domains - physiology; Proteins; Proteomics; Rats; Rats, Sprague-Dawley; Receptors; RNA Interference; RNA, Small Interfering - genetics; Signal Transduction - physiology; Signaling; Smoking; Titration; Titration calorimetry; Up-Regulation; α7nAChRs; PDZ domain; PDLIM5; Nicotine
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-021-04115-y

Nicotinic acetylcholine receptors (nAChRs) are widespread throughout the central nervous system. Signaling through nAChRs contributes to numerous higher-order functions, including memory and cognition, as well as abnormalities such as nicotine addiction and neurodegenerative disorders. 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 remain unclear. Here, we show that the PDZ-LIM domain family protein PDLIM5 binds to α7nAChRs and plays a role in nicotine-induced α7nAChRs upregulation and surface expression. We find that chronic exposure to 1 μM nicotine upregulated α7, β2-contained nAChRs and PDLIM5 in cultured hippocampal neurons, and the upregulation of α7nAChRs and PDLIM5 is increased more on the cell membrane than the cytoplasm. Interestingly, in primary hippocampal neurons, α7nAChRs and β2nAChRs display distinct patterns of expression, with α7nAChRs colocalized more with PDLIM5. Furthermore, PDLIM5 interacts with α7nAChRs, but not β2nAChRs in native brain neurons. Knocking down of PDLIM5 in SH-SY5Y abolishes nicotine-induced upregulation of α7nAChRs. In primary hippocampal neurons, using shRNA against PDLIM5 decreased both surface clustering of α7nAChRs and α7nAChRs-mediated currents. Proteomics analysis and isothermal titration calorimetry (ITC) results show that 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 the regulation of α7nAChRs, which may be relevant to plastic changes in the nervous system.