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

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.