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

Biochem Biophys Res Commun. 2019 Mar 12;510(3):370-375. doi: 10.1016/j.bbrc.2019.01.093. Epub 2019 Jan 31.

Abstract

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.

Keywords: 5-HT; 5-HT(1A)R; Cdk5; Phosphorylation; Proteasomal degradation; Serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • COS Cells
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Cricetulus
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Down-Regulation
  • HEK293 Cells
  • Humans
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism*
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin / pharmacology
  • Signal Transduction

Substances

  • Nerve Tissue Proteins
  • neuronal Cdk5 activator (p25-p35)
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Cyclin-Dependent Kinase 5
  • Proteasome Endopeptidase Complex