突触后电位
支架蛋白
突触后密度
谷氨酸受体
神经科学
脚手架
受体
化学
生物
医学
细胞生物学
生物化学
信号转导
生物医学工程
作者
Nicole Fadahunsi,Jonas Petersen,Sophia Metz,Alexander Jakobsen,Cecilie Vad Mathiesen,Alberte Silke Buch-Rasmussen,Nigel Kurgan,Jeppe Kjærgaard Larsen,Rita C. Andersen,Thomas Topilko,Charlotte Svendsen,Mia Apuschkin,Grethe Skovbjerg,Jan Hendrik Schmidt,Grace Houser,Sara Buskbjerg Jager,Anders Bach,Atul S. Deshmukh,Tuomas O. Kilpeläinen,Kristian Strømgaard,Kenneth L. Madsen,Christoffer Clemmensen
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-01
卷期号:10 (9)
标识
DOI:10.1126/sciadv.adg2636
摘要
Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N -methyl- d -aspartate (NMDA) receptors. Loci in/near discs large homolog 4 ( DLG4 ) and protein interacting with C kinase 1 ( PICK1 ) reached genome-wide significance ( P < 5 × 10 − 8 ) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4 ) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain–targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.
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