期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2119237119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Neuromodulation is pivotal for brain function. One of the key pathways engaged by neuromodulators is signaling via second messenger cAMP, which controls a myriad of fundamental reactions. This study identifies KCTD5, a ubiquitin ligase adapter, as a regulatory element in this pathway and determines that it works by an unusual dual mode controlling the activity of cAMP-generating enzyme in neurons through both zinc transport and G protein signaling.
Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger with an essential role in neuronal function. cAMP synthesis by adenylyl cyclases (AC) is controlled by G protein–coupled receptor (GPCR) signaling systems. However, the network of molecular players involved in the process is incompletely defined. Here, we used CRISPR/Cas9–based screening to identify that members of the potassium channel tetradimerization domain (KCTD) family are major regulators of cAMP signaling. Focusing on striatal neurons, we show that the dominant isoform KCTD5 exerts its effects through an unusual mechanism that modulates the influx of Zn
2+ via the Zip14 transporter to exert unique allosteric effects on AC. We further show that KCTD5 controls the amplitude and sensitivity of stimulatory GPCR inputs to cAMP production by Gβγ-mediated AC regulation. Finally, we report that KCTD5 haploinsufficiency in mice leads to motor deficits that can be reversed by chelating Zn
2+. Together, our findings uncover KCTD proteins as major regulators of neuronal cAMP signaling via diverse mechanisms.
