Novel Roles of Cdk5 and DISC1 in the Neurotransmitter Receptor-Mediated Signaling

Abstract

Identifying novel regulatory mechanisms of neurotransmitter receptor-mediated signaling has great importance in understanding various physiological phenomena in the brain. Neurotransmitters, released from the presynaptic neurons, transfer information to the postsynaptic neurons through specific receptors. Each neuron communicates with adjacent neurons through complex but highly organized neurotransmissions. In this study, we identified novel roles of cyclin-dependent kinase 5 (Cdk5), a neuronal specific proline-directed serine/threonine kinase, and Disrupted-in-schizophrenia 1 (DISC1), a major genetic factor of mental illnesses, in the dopamine receptor and GABA receptor-mediated signaling pathway, respectively.The dopamine D2 receptor (DRD2) is a key receptor that mediates dopamine-associated brain functions such as controlling mood, reward, and emotion. 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 for Cdk5. Cdk5 directly phosphorylates S321 and the phosphorylation impairs the agonist-stimulated surface expression of DRD2 accompanied with a decrease in G protein coupling to DRD2. Moreover, the downstream cAMP pathway was affected in the heterologous system and in primary cultured neurons 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. GABA is a major inhibitory neurotransmitter which is involved in the development of newborn neurons and regulation of neuronal excitability. DISC1 is a schizophrenia susceptible gene that plays critical roles in the neurodevelopment and various cellular functions. Although intimate correlations between GABA signaling and DISC1 have been postulated, contribution of DISC1 in the GABA signaling at the molecular level is not much elucidated. In this study, we identified abnormalities in the GABA signaling-related social behavior and anxiety behavior in a DISC1 mutant mouse line. Furthermore, GABA-induced currents and calcium dynamics in cultured hippocampal neurons of the DISC1 mutant mice were increased, which could be also recapitulated by changes in DISC1 expression in a wild type cultured hippocampal neurons. These results imply a novel role of DISC1 in the GABA-induced neuronal activity and calcium homeostasis. We identified novel roles of Cdk5 and DISC1 in the receptor-mediated signaling by the two studies

Cdk5 phosphorylates DRD2 and down-regulates DRD2-mediated downstream signaling, and DISC1 abnormality interrupts GABA-induced current and calcium dynamics. These results may provide expanded views of understanding receptor-mediated signaling in the brain.