视觉光转导
安普克
异三聚体G蛋白
细胞生物学
蛋白激酶A
神经退行性变
基因亚型
生物
AMP活化蛋白激酶
激酶
生物化学
信号转导
视网膜
G蛋白
内科学
基因
疾病
医学
作者
Tae Jun Lee,Yo Sasaki,Philip A. Ruzycki,Norimitsu Ban,Jaw‐Ren Lin,Howie Wu,Andrea Santeford,Rajendra S. Apte
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-01-16
标识
DOI:10.1172/jci.insight.173707
摘要
AMP-activated protein kinase (AMPK) plays a crucial role in maintaining ATP homeostasis in photoreceptor neurons. AMPK is a heterotrimeric protein consisting of alpha, beta, and gamma subunits. The independent functions of the two isoforms of the catalytic alpha subunit, PRKAA1 and PRKAA2, are uncharacterized in specialized neurons such as photoreceptors. Here we demonstrate in mice that rod photoreceptors lacking PRKAA2, but not PRKAA1, show altered levels of cGMP, GTP, and ATP, suggesting isoform-specific regulation of photoreceptor metabolism. Furthermore, PRKAA2 deficient mice display visual functional deficits on electroretinography and photoreceptor outer segment structural abnormalities on transmission electron microscopy consistent with neuronal dysfunction, but not neurodegeneration. Phosphoproteomics identified inosine monophosphate dehydrogenase (IMPDH) as a molecular driver of PRKAA2-specific photoreceptor dysfunction, and inhibition of IMPDH improved visual function in Prkaa2 rod photoreceptor knockout mice. These findings highlight a novel, therapeutically targetable PRKAA2 isoform-specific function of AMPK in regulating photoreceptor metabolism and function through a previously uncharacterized mechanism affecting IMPDH activity.
科研通智能强力驱动
Strongly Powered by AbleSci AI