title: Cdk5 phosphorylates dopamine D2 receptor and attenuates downstream signaling.
abstract: The dopamine D2 receptor (DRD2) is a key receptor that mediates dopamine-associated brain functions such as mood, reward, and emotion. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase whose function has been implicated in the brain reward circuit. In this study, we revealed that the serine 321 residue (S321) in the third intracellular loop of DRD2 (D2i3) is a novel regulatory site of Cdk5. Cdk5-dependent phosphorylation of S321 in the D2i3 was observed in in vitro and cell culture systems. We further observed that the phosphorylation of S321 impaired the agonist-stimulated surface expression of DRD2 and decreased G protein coupling to DRD2. Moreover, the downstream cAMP pathway was affected in the heterologous system and in primary neuronal cultures from p35 knockout embryos likely due to the reduced inhibitory activity of DRD2. These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Young-Un
authors.initials: YU
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Dae-Kyum
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Saebom
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Yongdo
authors.initials: Y
authors.lastname: Kwak
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Seol-Ae
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Haeryun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Korea Brain Research Institute, Daegu, Republic of Korea.
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Yong Song
authors.initials: YS
authors.lastname: Gho
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Sang Ki
authors.initials: SK
authors.lastname: Park
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics; D002853:Chromatography, Liquid; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism; D005838:Genotype; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D017448:Receptors, Dopamine D2; D051360:Cyclin-Dependent Kinase 5; D019204:GTP-Binding Proteins