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Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT1A receptor via phosphorylation

Takahashi, Miyuki, Kobayashi, Yuki, Ando, Kanae, Saito, Yumiko, Hisanaga, Shin-ichi
Biochemical and biophysical research communications 2019 v.510 no.3 pp. 370-375
G-protein coupled receptors, G-proteins, behavior disorders, brain, cyclic AMP, cyclin-dependent kinase, mammals, neurotransmitters, neutralization, phosphorylation, proteasome endopeptidase complex, serotonin
Serotonin (5-HT) is a major neurotransmitter in mammalian brains and is involved in brain development and psychiatric disorders. The 5-HT1A receptor (5-HT1AR) is a G-protein-coupled receptor (GPCR) associated with an inhibitory G-protein (Gi) with the widest and most abundant expression. It is not known; however, how expression or activity of 5-HTlAR is regulated. We studied here phosphorylation of 5-HT1AR 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-HT1AR was phosphorylated by the Cdk5–p35 complex at Thr314 in the third cytoplasmic loop. The phosphorylation stimulated the degradation of 5-HT1AR by the proteasome, resulting in neutralization of the inhibitory action of 5-HT1AR on intracellular cAMP concentration. These results suggest that Cdk5–p35 modulates 5-HT signaling through phosphorylation-dependent degradation of 5-HTlAR.