Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, 192-0397, Japan.
Graduate School Integrated Arts and Sciences, Hiroshima University, Hiroshima, 739-8521, Japan.
Biochem Biophys Res Commun. 2019 Mar 12;510(3):370-375. doi: 10.1016/j.bbrc.2019.01.093. Epub 2019 Jan 31.
Serotonin (5-HT) is a major neurotransmitter in mammalian brains and is involved in brain development and psychiatric disorders. The 5-HT receptor (5-HTR) is a G-protein-coupled receptor (GPCR) associated with an inhibitory G-protein (G) with the widest and most abundant expression. It is not known; however, how expression or activity of 5-HTR is regulated. We studied here phosphorylation of 5-HTR by cyclin-dependent kinase 5 (Cdk5), a neuron-specific membrane-bound Ser/Thr kinase that is activated by binding of the p35 Cdk5 activator. 5-HTR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop. The phosphorylation stimulated the degradation of 5-HTR by the proteasome, resulting in neutralization of the inhibitory action of 5-HTR on intracellular cAMP concentration. These results suggest that Cdk5-p35 modulates 5-HT signaling through phosphorylation-dependent degradation of 5-HTR.
血清素（5-HT）是哺乳动物大脑中的一种主要神经递质，参与脑发育和精神疾病。5-HT 受体（5-HTR）是一种与抑制性 G 蛋白（G）相关的 G 蛋白偶联受体（GPCR），其表达最广泛、最丰富。然而，目前尚不清楚 5-HTR 的表达或活性是如何调节的。我们在这里研究了周期蛋白依赖性激酶 5（Cdk5）对 5-HTR 的磷酸化作用，Cdk5 是一种神经元特异性膜结合 Ser/Thr 激酶，通过与 p35 Cdk5 激活剂结合而被激活。Cdk5-p35 复合物在第三胞质环中的 Thr314 处磷酸化 5-HTR。磷酸化刺激 5-HTR 通过蛋白酶体降解，导致 5-HTR 对细胞内 cAMP 浓度的抑制作用中和。这些结果表明，Cdk5-p35 通过 5-HTR 的磷酸化依赖性降解来调节 5-HT 信号。
