Sloan Douglas C, Liao Yini, Ray Forest, Muntean Brian S
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.
PLoS Biol. 2025 Apr 15;23(4):e3003117. doi: 10.1371/journal.pbio.3003117. eCollection 2025 Apr.
G proteins (Gα and Gβγ subtypes) drive adenylyl cyclase type 5 (AC5) synthesis of cAMP in striatal neurons, which is essential for motor coordination. KCTD5 directly interacts with Gβγ to delimit signaling events, yet downstream impact of KCTD5 in striatal circuits is not known. Here, generation of a conditional Kctd5 knockout mouse identified that loss of striatal KCTD5 leads to a dystonic phenotype, coordination deficits, and skewed transitions between behavioral syllables. 2-photon imaging of a cAMP biosensor revealed electrically evoked dopaminergic responses were significantly augmented in the absence of KCTD5 in striatal circuits. cAMP sensitization was rescued in situ by expression of a Gβγ-scavenging nanobody and motor deficits were partially rescued in vivo by pharmacological antagonism of the indirect striatal cAMP pathway. Therefore, KCTD5 acts as a brake on cAMP signaling in striatal neurons important for tuning dopaminergic signaling and motor coordination.
G蛋白（Gα和Gβγ亚型）驱动纹状体神经元中5型腺苷酸环化酶（AC5）合成环磷酸腺苷（cAMP），这对运动协调至关重要。KCTD5直接与Gβγ相互作用以限制信号转导事件，但KCTD5在纹状体回路中的下游影响尚不清楚。在这里，通过生成条件性Kctd5基因敲除小鼠发现，纹状体KCTD5的缺失会导致肌张力障碍表型、协调缺陷以及行为音节之间的过渡偏差。对cAMP生物传感器进行双光子成像显示，在纹状体回路中缺乏KCTD5的情况下，电诱发的多巴胺能反应显著增强。通过表达一种清除Gβγ的纳米抗体可在原位挽救cAMP致敏，并且通过间接纹状体cAMP途径的药理学拮抗作用可在体内部分挽救运动缺陷。因此，KCTD5在纹状体神经元中作为cAMP信号的制动器，对调节多巴胺能信号和运动协调很重要。
